bims-flamet 2024-02-11 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–02–11
38 papers selected by
Peio Azcoaga, Biodonostia HRI

Advance in the role of chemokines/chemokine receptors in carcinogenesis: Focus on pancreatic cancer.
Measurement of Metabolic Alteration in Immune Cells Under Hypoxia.
Regulation of T cells in the tumor microenvironment by histone methylation: LSD1 inhibition-a new direction for enhancing immunotherapy.
The cellular triumvirate: fibroblasts entangled in the crosstalk between cancer cells and immune cells.
Extracellular matrix remodeling in the tumor immunity.
IL-1 Family Members in Bone Sarcomas.
The Role of Chemokines in Orchestrating the Immune Response to Pancreatic Ductal Adenocarcinoma.
Editorial: Community series in unveiling the tumor microenvironment by machine learning to develop new immunotherapeutic strategies, volume II.
Breast Cancer Stem Cells Secrete MIF to Mediate Tumor Metabolic Reprogramming that Drives Immune Evasion.
The suppressive tumor microenvironment of AFP-positive hepatocellular carcinoma and its therapeutic implications.
The RNA m6A writer METTL3 in tumor microenvironment: emerging roles and therapeutic implications.
A promising target for breast cancer: B7-H3.
B10 cells: Development, phenotype, and function in cancer.
Macrophages as targets in hepatocellular carcinoma therapy.
The regulatory role and mechanism of mast cells in tumor microenvironment.
Mechanisms of Altered Immune Response in Skin Melanoma.
PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy.
[Hepatocellular Carcinoma-Derived Exosomes: Key Players in Intercellular Communication Within the Tumor Microenvironment].
Role of T cells in cancer immunotherapy: Opportunities and challenges.
Clinical Potential of YY1-Hypoxia Axis for Vascular Normalization and to Improve Immunotherapy.
Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer.
Triple-Negative Breast Cancer Intrinsic FTSJ1 Favors Tumor Progression and Attenuates CD8+ T Cell Infiltration.
Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.
Harnessing Chimeric Antigen Receptor-engineered Invariant Natural Killer T Cells: Therapeutic Strategies for Cancer and the Tumor Microenvironment.
The Aryl Hydrocarbon Receptor: Impact on the Tumor Immune Microenvironment and Modulation as a Potential Therapy.
Rethinking the roles of cancer associated fibroblasts in pancreatic cancer.
Fibroblasts: invigorated targets in pre-metastatic niche formation.
IR-780 Dye-based Targeting of Cancer-associated Fibroblasts Improves Cancer Immunotherapy by Increasing Intra-tumoral T Lymphocytes Infiltration.
The Role of Neutrophil Extracellular Traps in the Outcome of Malignant Epitheliomas: Significance of CA215 Involvement.
Comprehensive analysis of ALG3 in pan-cancer and validation of ALG3 as an onco-immunological biomarker in breast cancer.
Single-Cell Characterization of the Tumor Ecosystem in Liver Cancer.
What's new about the tumor microenvironment of urothelial carcinoma?
PD-L2 expression in senescent cancer cells limits tumor clearance after chemotherapy.
Hypoxia: Intriguing Feature in Cancer Cell Biology.
M2 tumor-associated macrophages and CXCL2 induce lipid remodeling in hepatocellular carcinoma cell lines.
The impact of Foxp3+ regulatory T-cells on CD8+ T-cell dysfunction in tumour microenvironments and responses to immune checkpoint inhibitors.
Tissue damage from chronic liver injury inhibits peripheral NK cell abundance and proinflammatory function.
Lipid droplets provide metabolic flexibility for cancer progression.

Eur J Pharmacol. 2024 Feb 01. pii: S0014-2999(24)00045-1. [Epub ahead of print]967 176357

Advance in the role of chemokines/chemokine receptors in carcinogenesis: Focus on pancreatic cancer.

Na Song, Kai Cui, Liqun Zeng, Mengxiao Li, Yanwu Fan, Pingyu Shi, Ziwei Wang, Wei Su, Haijun Wang.

  The chemokines/chemokine receptors pathway significantly influences cell migration, particularly in recruiting immune cells to the tumor microenvironment (TME), impacting tumor progression and treatment outcomes. Emerging research emphasizes the involvement of chemokines in drug resistance across various tumor therapies, including immunotherapy, chemotherapy, and targeted therapy. This review focuses on the role of chemokines/chemokine receptors in pancreatic cancer (PC) development, highlighting their impact on TME remodeling, immunotherapy, and relevant signaling pathways. The unique immunosuppressive microenvironment formed by the interaction of tumor cells, stromal cells and immune cells plays an important role in the tumor proliferation, invasion, migration and therapeutic resistance. Chemokines/chemokine receptors, such as chemokine ligand (CCL) 2, CCL3, CCL5, CCL20, CCL21, C-X-C motif chemokine ligand (CXCL) 1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL16, CXCL17, and C-X3-C motif chemokine ligand (CX3CL)1, derived mainly from leukocyte cells, cancer-related fibroblasts (CAFs), pancreatic stellate cells (PSCs), and tumor-associated macrophages (TAMs), contribute to PC progression and treatment resistance. Chemokines recruit myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs), and M2 macrophages, inhibiting the anti-tumor activity of immune cells. Simultaneously, they enhance pathways like epithelial-mesenchymal transition (EMT), Akt serine/threonine kinase (AKT), extracellular regulated protein kinases (ERK) 1/2, and nuclear factor kappa-B (NF-κB), etc., elevating the risk of PC metastasis and compromising the efficacy of radiotherapy, chemotherapy, and anti-PD-1/PD-L1 immunotherapy. Notably, the CCLx-CCR2 and CXCLx-CXCR2/4 axis emerge as potential therapeutic targets in PC. This review integrates recent findings on chemokines and receptors in PC treatment, offering valuable insights for innovative therapeutic approaches.

Keywords:  Carcinogenesis; Chemokine receptors; Chemokines; Immunotherapy; Microenvironment; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.ejphar.2024.176357
Methods Mol Biol. 2024 ;2755 201-212

Measurement of Metabolic Alteration in Immune Cells Under Hypoxia.

Yuki Fujii, Kamiya Mehla.

  The hypoxic microenvironment in solid tumors affects the metabolism of tumor cells and infiltrating immune cells, which aids in robust tumor growth and expansion. Myeloid-derived suppressor cells (MDSCs) are heterogenous immature myeloid cells in the TME, which play an essential role in immune evasion by subverting T/NK cell-mediated killing. The immunosuppressive function of MDSCs is tightly regulated to the metabolic pathways, in which hypoxia plays a critical role. In this chapter, we describe the isolation of murine MDSCs from bone marrows and the measurement of the transcriptomic changes of essential metabolic enzymes under hypoxic conditions. This method can be applied to study MDSCs function, mimicking the hypoxic environment in vitro. This method can be utilized to investigate the critical metabolic alterations under a given tumor context and help evaluate the efficacy of metabolic-targeted therapies in the long run.

Keywords:  Cancer; Glycolysis; Hypoxia; Myeloid-derived suppressor cell; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-1-0716-3633-6_15
Heliyon. 2024 Jan 30. 10(2): e24457

Regulation of T cells in the tumor microenvironment by histone methylation: LSD1 inhibition-a new direction for enhancing immunotherapy.

Xie Xueqing, Peng Yongcan, Lu Wei, Yin Qingling, Ding Jie.

  Although immune checkpoint blockade (ICB) has been shown to achieve durable therapeutic responses in various types of tumors, only 20-40 % of patients benefit from this therapy. A growing body of research suggests that epigenetic modulation of the tumor microenvironment may be a promising direction for enhancing the efficacy of immunotherapy, for example, histone methylation plays an important role in the regulation of T cells in the tumor microenvironment (TME). In particular, histone lysine-specific demethylase 1 (LSD1/KDM1A), as an important histone-modifying enzyme in epigenetics, was found to be an important factor in the regulation of T cells. Therefore, this paper will summarize the effects of histone methylation, especially LSD1, on T cells in the TME to enhance the efficacy of anti-PD-1 immunotherapy. To provide a strong theoretical basis for the strategy of combining LSD1 inhibitors with anti-PD-1/PD-L1 immunotherapy, thus adding new possibilities to improve the survival of tumor patients.

Keywords:  Anti-PD-1; Anti-Tumor immunity; CD8+ T cells; Histone methylation; LSD1; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.heliyon.2024.e24457
Front Immunol. 2023 ;14 1337333

The cellular triumvirate: fibroblasts entangled in the crosstalk between cancer cells and immune cells.

Adel Fergatova, Nesrine I Affara.

  This review article will focus on subpopulations of fibroblasts that get reprogrammed by tumor cells into cancer-associated fibroblasts. Throughout this article, we will discuss the intricate interactions between fibroblasts, immune cells, and tumor cells. Unravelling complex intercellular crosstalk will pave the way for new insights into cellular mechanisms underlying the reprogramming of the local tumor immune microenvironment and propose novel immunotherapy strategies that might have potential in harnessing and modulating immune system responses.

Keywords:  cancer-associated fibroblasts; fibroblasts; heterogeneity; immunosuppression; reprogramming

DOI:  https://doi.org/10.3389/fimmu.2023.1337333
Front Immunol. 2023 ;14 1340634

Extracellular matrix remodeling in the tumor immunity.

Wei Du, Xueming Xia, Fan Hu, Jiayun Yu.

  The extracellular matrix (ECM) is a significant constituent of tumors, fulfilling various essential functions such as providing mechanical support, influencing the microenvironment, and serving as a reservoir for signaling molecules. The abundance and degree of cross-linking of ECM components are critical determinants of tissue stiffness. In the process of tumorigenesis, the interaction between ECM and immune cells within the tumor microenvironment (TME) frequently leads to ECM stiffness, thereby disrupting normal mechanotransduction and promoting malignant progression. Therefore, acquiring a thorough comprehension of the dysregulation of ECM within the TME would significantly aid in the identification of potential therapeutic targets for cancer treatment. In this regard, we have compiled a comprehensive summary encompassing the following aspects: (1) the principal components of ECM and their roles in malignant conditions; (2) the intricate interaction between ECM and immune cells within the TME; and (3) the pivotal regulators governing the onco-immune response in ECM.

Keywords:  cancer; extracellular matrix; immune cells; stiffness; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1340634
Cells. 2024 Jan 25. pii: 233. [Epub ahead of print]13(3):

IL-1 Family Members in Bone Sarcomas.

Lorena Landuzzi, Francesca Ruzzi, Evelin Pellegrini, Pier-Luigi Lollini, Katia Scotlandi, Maria Cristina Manara.

  IL-1 family members have multiple pleiotropic functions affecting various tissues and cells, including the regulation of the immune response, hematopoietic homeostasis, bone remodeling, neuronal physiology, and synaptic plasticity. Many of these activities are involved in various pathological processes and immunological disorders, including tumor initiation and progression. Indeed, IL-1 family members have been described to contribute to shaping the tumor microenvironment (TME), determining immune evasion and drug resistance, and to sustain tumor aggressiveness and metastasis. This review addresses the role of IL-1 family members in bone sarcomas, particularly the highly metastatic osteosarcoma (OS) and Ewing sarcoma (EWS), and discusses the IL-1-family-related mechanisms that play a role in bone metastasis development. We also consider the therapeutic implications of targeting IL-1 family members, which have been proposed as (i) relevant targets for anti-tumor and anti-metastatic drugs; (ii) immune checkpoints for immune suppression; and (iii) potential antigens for immunotherapy.

Keywords:  Ewing sarcoma; IL-1 family; IL-1RAP; bone metastasis; chimeric-antigen-receptor-modified effectors; cytokines; immune escape; macrophages; osteosarcoma; tumor microenvironment

DOI:  https://doi.org/10.3390/cells13030233
Cancers (Basel). 2024 Jan 28. pii: 559. [Epub ahead of print]16(3):

The Role of Chemokines in Orchestrating the Immune Response to Pancreatic Ductal Adenocarcinoma.

Alexander A Lekan, Louis M Weiner.

  Chemokines are small molecules that function as chemotactic factors which regulate the migration, infiltration, and accumulation of immune cells. Here, we comprehensively assess the structural and functional role of chemokines, examine the effects of chemokines that are present in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME), specifically those produced by cancer cells and stromal components, and evaluate their impact on immune cell trafficking, both in promoting and suppressing anti-tumor responses. We further explore the impact of chemokines on patient outcomes in PDAC and their role in the context of immunotherapy treatments, and review clinical trials that have targeted chemokine receptors and ligands in the treatment of PDAC. Lastly, we highlight potential strategies that can be utilized to harness chemokines in order to increase cytotoxic immune cell infiltration and the anti-tumor effects of immunotherapy.

Keywords:  T cell; cancer-associated fibroblasts (CAFs); chemokine; immunotherapy; natural killer (NK) cells; pancreatic ductal adenocarcinoma (PDAC); tumor microenvironment (TME); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3390/cancers16030559
Front Immunol. 2024 ;15 1351597

Editorial: Community series in unveiling the tumor microenvironment by machine learning to develop new immunotherapeutic strategies, volume II.

Ping Zheng, Jun Liu.



Keywords:  disease; immune infiltrations; machine learning; tumor; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1351597
Cancer Res. 2024 Feb 09.

Breast Cancer Stem Cells Secrete MIF to Mediate Tumor Metabolic Reprogramming that Drives Immune Evasion.

Linlin Yan, Mingming Wu, Tianyu Wang, Hui Yuan, Xiao Zhang, Huafeng Zhang, Tao Li, Vijay Pandey, Xinghua Han, Peter E Lobie, Tao Zhu.

Reprogramming of energy metabolism exerts pivotal functions in cancer progression and immune surveillance. Identification of the mechanisms mediating metabolic changes in cancer may lead to improved strategies to suppress tumor growth and stimulate anti-tumor immunity. Here, it was observed that the secretomes of hypoxic breast cancer cells and breast cancer stem cells (BCSCs) induced reprogramming of metabolic pathways, particularly glycolysis, in normoxic breast cancer cells. Screening of the BCSC secretome identified MIF as a pivotal factor potentiating glycolysis. Mechanistically, MIF increased c-MYC-mediated transcriptional upregulation of the glycolytic enzyme aldolase C by activating WNT/β-CATENIN signaling. Targeting MIF attenuated glycolysis and impaired xenograft growth and metastasis. MIF depletion in breast cancer cells also augmented intratumoral cytolytic CD8+ T cells and pro-inflammatory macrophages while decreasing Tregs and tumor-associated neutrophils in the tumor microenvironment. Consequently, targeting MIF improved the therapeutic efficacy of immune checkpoint blockade (ICB) in triple-negative breast cancer. Collectively, this study proposes MIF as an attractive therapeutic target to circumvent metabolic reprogramming and immunosuppression in breast cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2390
Transl Gastroenterol Hepatol. 2024 ;9 1

The suppressive tumor microenvironment of AFP-positive hepatocellular carcinoma and its therapeutic implications.

Isabella Lurje, Linda Hammerich.



Keywords:  Hepatocellular carcinoma (HCC); alpha-fetoprotein (AFP); immunotherapy; tumor microenvironment (TME)

DOI:  https://doi.org/10.21037/tgh-23-81
Front Immunol. 2024 ;15 1335774

The RNA m6A writer METTL3 in tumor microenvironment: emerging roles and therapeutic implications.

Weiqi Su, Lin Che, Wenting Liao, Huilin Huang.

  The tumor microenvironment (TME) is a heterogeneous ecosystem comprising cancer cells, immune cells, stromal cells, and various non-cellular components, all of which play critical roles in controlling tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), the core component of N 6-methyladenosine (m6A) writer, is frequently associated with abnormalities in the m6A epitranscriptome in different cancer types, impacting both cancer cells and the surrounding TME. While the impact of METTL3 on cancer cells has been extensively reviewed, its roles in TME and anti-cancer immunity have not been comprehensively summarized. This review aims to systematically summarize the functions of METTL3 in TME, particularly its effects on tumor-infiltrating immune cells. We also elaborate on the underlying m6A-dependent mechanism. Additionally, we discuss ongoing endeavors towards developing METTL3 inhibitors, as well as the potential of targeting METTL3 to bolster the efficacy of immunotherapy.

Keywords:  N6-methyladenosine (m6A); cancer immunotherapy; immune checkpoint inhibitors (ICI); methyltransferase-like 3 (METTL3); small molecular inhibitors; tumor-infiltrating immune cells (TICs)

DOI:  https://doi.org/10.3389/fimmu.2024.1335774
BMC Cancer. 2024 Feb 07. 24(1): 182

A promising target for breast cancer: B7-H3.

Ying Jiang, Jiayu Liu, Lingyan Chen, Zhiwen Qian, Yan Zhang.

  Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint.In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.

Keywords:  B7-H3; Breast cancer; Cancer immunotherapy; Immune checkpoint; Targeted immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12885-024-11933-3
Adv Clin Exp Med. 2024 Feb 05.

B10 cells: Development, phenotype, and function in cancer.

Dandan Li, Yunfeng Ma.

  B10 cells, a specialized subset of regulatory B cells, have been identified in both mice and humans. These cells are characterized by their regulatory impact on immune dynamics, principally through their secretion of interleukin-10 (IL-10), a cytokine known for its anti-inflammatory properties. The pivotal role of immune mediators such as B10 cells is to maintain a delicate equilibrium between antitumor immunity and tumor-promoting responses. Emerging studies have cast B10 cells as key suppressors in the antitumor immune arsenal. They operate in synergy with a spectrum of immune cells within the innate and adaptive spectrums, contributing to a milieu that favors tumor progression and metastatic spread. In this comprehensive review, we will discuss the ontogeny, phenotype and effector functions of B10 cells in murine systems. We will also review the role of B10 cells in oncological models in animal studies and extend these findings to the human clinical context, elucidating their role in facilitating tumor immune evasion. A thorough understanding of these processes is imperative for the strategic targeting and attenuation of B10 cell activity, which is anticipated to be a cornerstone in the advancement of effective cancer immunotherapy strategies.

Keywords:  B10 cells; IL-10; cancer; tumor immunology

DOI:  https://doi.org/10.17219/acem/176378
Mol Cancer Ther. 2024 Feb 03.

Macrophages as targets in hepatocellular carcinoma therapy.

Yu-Ting Liu, Zheng-Wei Mao, Yuan Ding, Wei-Lin Wang.

Hepatocellular carcinoma (HCC) is a malignant tumor with a complex and diverse immunosuppressive microenvironment. Tumor-associated macrophages (TAMs) are an essential component of the tumor immune microenvironment. TAMs typically exist in two primary states: anti-tumor M1 macrophages and pro-tumor M2 macrophages. Remarkably, TAMs possess high plasticity, enabling them to switch between different subtypes or alter their biological functions in response to the tumor microenvironment. Based on research into the biological role of TAMs in the occurrence and development of malignant tumors, including HCC, TAMs are emerging as promising targets for novel tumor treatment strategies. In this review, we provide a detailed introduction to the origin and subtypes of TAMs, elucidate their interactions with other cells in the complex tumor microenvironment of HCC, and describe the biological roles, characteristics, and mechanisms of TAMs in the progression of HCC. Furthermore, we furnish an overview of the latest therapeutic strategies targeting TAMs.

DOI: https://doi.org/10.1158/1535-7163.MCT-23-0660
Am J Cancer Res. 2024 ;14(1): 1-15

The regulatory role and mechanism of mast cells in tumor microenvironment.

Caryl Ligan, Xin-Hua Ma, Shu-Li Zhao, Wei Zhao.

Mast cells (MCs) have emerged as pivotal contributors to both the defensive immune response and immunomodulation. They also exhibit regulatory functions in modulating pathological processes across various allergic diseases. The impact of MC presence within tumor tissues has garnered considerable attention, yielding conflicting findings. While some studies propose that MCs within tumor tissues promote tumor initiation and progression, others advocate an opposing perspective. Notably, evidence emphasizes the dual role of MCs in cancer, both as promoters and suppressors, is crucial for optimizing cancer treatment strategies. These conflicting viewpoints have generated substantial controversy, underscoring the need for a comprehensive understanding of MC's role in tumor immune responses.

Keywords: Mast cells; immunomodulation; tumor microenvironment
Curr Health Sci J. 2023 Jul-Sep;49(3):49(3): 297-311

Mechanisms of Altered Immune Response in Skin Melanoma.

Radu-Florin Fruntealată, Matei Marius, Ianis Kevyn Stefan Boboc, Smaranda Ioana Mitran, Marius Eugen Ciurea, George-Alin Stoica.

  Melanoma, a deadly form of skin cancer, poses significant challenges to the host immune system, allowing tumor cells to evade immune surveillance and persist. This complex interplay between melanoma and the immune system involves a multitude of mechanisms that impair immune recognition and promote tumor progression. This review summarizes the intricate strategies employed by melanoma cells to evade the immune response, including defective immune recognition, immune checkpoint activation, and the role of regulatory T-cells, myeloid-derived suppressor cells, and exosomes in suppressing anti-tumor immunity. Additionally, we discuss potential therapeutic targets aimed at reversing immune evasion in melanoma, highlighting the importance of understanding these mechanisms for developing more effective immunotherapies. Improved insights into the interactions between melanoma and the immune system will aid in the development of novel treatment strategies to enhance anti-tumor immune responses and improve patient outcomes.

Keywords:   Melanoma ; immune response ; skin cancer

DOI:  https://doi.org/10.12865/CHSJ.49.03.01
J Exp Med. 2024 Mar 04. pii: e20231519. [Epub ahead of print]221(3):

PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy.

Lei Wang, Yufeng Xiao, Yuewan Luo, Rohan P Master, Jiao Mo, Myung-Chul Kim, Yi Liu, Chandra K Maharjan, Urvi M Patel, Umasankar De, Madison E Carelock, Tanzia Islam Tithi, Xiangming Li, Donald R Shaffer, Kevin R Guertin, Haoyang Zhuang, Emily Moser, Keiran S M Smalley, Dongwen Lv, Daohong Zhou, Guangrong Zheng, Weizhou Zhang.

An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.

DOI: https://doi.org/10.1084/jem.20231519
Sichuan Da Xue Xue Bao Yi Xue Ban. 2024 Jan 20. 55(1): 6-12

[Hepatocellular Carcinoma-Derived Exosomes: Key Players in Intercellular Communication Within the Tumor Microenvironment].

Tang Feng, Xinrui Yang, Qiwei Wang, Xiaoheng Liu.

  Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Due to the insidious onset and rapid progression and a lack of effective treatments, the prognosis of patients with HCC is extremely poor, with the average 5-year survival rate being less than 10%. The tumor microenvironment (TME), the internal environment in which HCC develops, can regulate the oncogenesis, development, invasion, and metastasis of HCC. During the process of cancer progression, HCC cells can regulate the biological behaviors of tumor cells, cancer-associated fibroblasts, cancer-associated immune cells, and other cells in the TME by releasing exosomes containing specific signals, thereby promoting cancer progression. However, the exact molecular mechanisms and the roles of exosomes in the specific cellular regulation of these processes are not fully understood. Herein, we summarized the TME components of HCC, the sources and the biological traits of exosomes in the TME, and the impact of mechanical factors on exosomes. In addition, special attention was given to the discussion of the effects of HCC-exosomes on different types of cells in the microenvironment. There are still many difficulties to be overcome before exosomes can be applied as carriers in clinical cancer treatment. First of all, the homogeneity of exosomes is difficult to ensure. Secondly, exosomes are mainly administered through subcutaneous injection. Although this method is simple and easy to implement, the absorption efficiency is not ideal. Thirdly, exosome extraction methods are limited in number and inefficient, making it difficult to prepare exosomes in large quantities. It is important to ensure that exosomes are used in sufficient quantities to trigger an effective tumor immune response, especially for exosome-mediated tumor immunotherapy. With the improvement in identification, isolation, and purification technology, exosomes are expected to be successfully used in the clinical diagnosis of early-stage HCC and the clinical treatment of liver cancer.

Keywords:  Exosomes; Hepatocellular carcinoma; Intercellular communication; Review; Tumor microenvironment

DOI:  https://doi.org/10.12182/20240160203
Cancer Pathog Ther. 2023 Apr;1(2): 116-126

Role of T cells in cancer immunotherapy: Opportunities and challenges.

Hossain Ahmed, Aar Rafi Mahmud, Mohd Faijanur-Rob- Siddiquee, Asif Shahriar, Partha Biswas, Md Ebrahim Khalil Shimul, Shahlaa Zernaz Ahmed, Tanzila Ismail Ema, Nova Rahman, Md Arif Khan, Md Furkanur Rahaman Mizan, Talha Bin Emran.

  Immunotherapies boosting the immune system's ability to target cancer cells are promising for the treatment of various tumor types, yet clinical responses differ among patients and cancers. Recently, there has been increasing interest in novel cancer immunotherapy practices aimed at triggering T cell-mediated anti-tumor responses. Antigen-directed cytotoxicity mediated by T lymphocytes has become a central focal point in the battle against cancer utilizing the immune system. The molecular and cellular mechanisms involved in the actions of T lymphocytes have directed new therapeutic approaches in cancer immunotherapy, including checkpoint blockade, adoptive and chimeric antigen receptor (CAR) T cell therapy, and cancer vaccinology. This review addresses all the strategies targeting tumor pathogenesis, including metabolic pathways, to evaluate the clinical significance of current and future immunotherapies for patients with cancer, which are further engaged in T cell activation, differentiation, and response against tumors.

Keywords:  Cancer; Immune system; Immunotherapy; Metabolic pathways; T cell

DOI:  https://doi.org/10.1016/j.cpt.2022.12.002
Cancers (Basel). 2024 Jan 23. pii: 491. [Epub ahead of print]16(3):

Clinical Potential of YY1-Hypoxia Axis for Vascular Normalization and to Improve Immunotherapy.

Concetta Meo, Filomena de Nigris.

  Abnormal vasculature in solid tumors causes poor blood perfusion, hypoxia, low pH, and immune evasion. It also shapes the tumor microenvironment and affects response to immunotherapy. The combination of antiangiogenic therapy and immunotherapy has emerged as a promising approach to normalize vasculature and unlock the full potential of immunotherapy. However, the unpredictable and redundant mechanisms of vascularization and immune suppression triggered by tumor-specific hypoxic microenvironments indicate that such combination therapies need to be further evaluated to improve patient outcomes. Here, we provide an overview of the interplay between tumor angiogenesis and immune modulation and review the function and mechanism of the YY1-HIF axis that regulates the vascular and immune tumor microenvironment. Furthermore, we discuss the potential of targeting YY1 and other strategies, such as nanocarrier delivery systems and engineered immune cells (CAR-T), to normalize tumor vascularization and re-establish an immune-permissive microenvironment to enhance the efficacy of cancer therapy.

Keywords:  hypoxia; immunotherapy; tumor vascularization

DOI:  https://doi.org/10.3390/cancers16030491
Front Microbiol. 2024 ;15 1325558

Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer.

Lisa A Santry, Jacob P van Vloten, Amanda W K AuYeung, Robert C Mould, Jacob G E Yates, Thomas M McAusland, James J Petrik, Pierre P Major, Byram W Bridle, Sarah K Wootton.

   Introduction: Tumor microenvironments are immunosuppressive due to progressive accumulation of mutations in cancer cells that can drive expression of a range of inhibitory ligands and cytokines, and recruitment of immunomodulatory cells, including myeloid-derived suppressor cells (MDSC), tumor-associated macrophages, and regulatory T cells (Tregs).
Methods: To reverse this immunosuppression, we engineered mesogenic Newcastle disease virus (NDV) to express immunological checkpoint inhibitors anti-cytotoxic T lymphocyte antigen-4 and soluble programmed death protein-1.
Results: Intratumoral administration of recombinant NDV (rNDV) to mice bearing intradermal B16-F10 melanomas or subcutaneous CT26LacZ colon carcinomas led to significant changes in the tumor-infiltrating lymphocyte profiles. Vectorizing immunological checkpoint inhibitors in NDV increased activation of intratumoral natural killer cells and cytotoxic T cells and decreased Tregs and MDSCs, suggesting induction of a pro-inflammatory state with greater infiltration of activated CD8+ T cells. These notable changes translated to higher ratios of activated effector/suppressor tumor-infiltrating lymphocytes in both cancer models, which is a promising prognostic marker. Whereas all rNDV-treated groups showed evidence of tumor regression and increased survival in the CT26LacZ and B16-F10, only treatment with NDV expressing immunological checkpoint blockades led to complete responses compared to tumors treated with NDV only.
Discussion: These data demonstrated that NDV expressing immunological checkpoint inhibitors could reverse the immunosuppressive state of tumor microenvironments and enhance tumor-specific T cell responses.

Keywords:  B16-F10; Newcastle disease virus (NDV); PD-1; PD-L1; anti-CTLA-4; immunological checkpoint inhibitors; oncolytic virus; tumor microenvironment

DOI:  https://doi.org/10.3389/fmicb.2024.1325558
Cancers (Basel). 2024 Jan 31. pii: 597. [Epub ahead of print]16(3):

Triple-Negative Breast Cancer Intrinsic FTSJ1 Favors Tumor Progression and Attenuates CD8+ T Cell Infiltration.

Yangqing Sun, Qingqing Liu, Shangwei Zhong, Rui Wei, Jun-Li Luo.

  FtsJ RNA 2'-O-methyltransferase 1 (FTSJ1) is a member of the methyltransferase superfamily and is involved in the processing and modification of ribosomal RNA. We herein demonstrate that FTSJ1 favors TNBC progression. The knockdown of FTSJ1 inhibits TNBC cell proliferation and development, induces apoptosis of cancer cells, and increases the sensitivity of TNBC cells to T-cell-mediated cytotoxicity. Furthermore, the high expression of FTSJ1 in TNBC attenuates CD8+T cell infiltration in the tumor microenvironment (TME) correlated with poorer prognosis for clinical TNBC patients. In this study, we establish that FTSJ1 acts as a tumor promotor, is involved in cancer immune evasion, and may serve as a potential immunotherapy target in TNBC.

Keywords:  CD8+T cell infiltration; FTSJ1; triple-negative breast cancer; tumor promotor

DOI:  https://doi.org/10.3390/cancers16030597
iScience. 2024 Feb 16. 27(2): 108879

Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.

Yufei Wang, Jae-Won Cho, Gabriella Kastrunes, Alicia Buck, Cecile Razimbaud, Aedin C Culhane, Jiusong Sun, David A Braun, Toni K Choueiri, Catherine J Wu, Kristen Jones, Quang-De Nguyen, Zhu Zhu, Kevin Wei, Quan Zhu, Sabina Signoretti, Gordon J Freeman, Martin Hemberg, Wayne A Marasco.

  One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule. G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8+ T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk.

Keywords:  Cancer; Immunology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.108879
Curr Pharm Biotechnol. 2024 Jan 16.

Harnessing Chimeric Antigen Receptor-engineered Invariant Natural Killer T Cells: Therapeutic Strategies for Cancer and the Tumor Microenvironment.

Yiqing Wang, Yan-Ruide Li.

  Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has emerged as a revolutionary approach for cancer treatment, especially for hematologic cancers. However, CAR-T therapy has some limitations, including cytokine release syndrome (CRS), immune cellassociated neurologic syndrome (ICANS), and difficulty in targeting solid tumors and delivering allogeneic cell therapy due to graft-versus-host disease (GvHD). Therefore, it is important to explore other cell sources for CAR engineering. Invariant natural killer T (iNKT) cells are a potential target, as they possess powerful antitumor ability and do not recognize mismatched major histocompatibility complexes (MHCs) and protein antigens, thus avoiding the risk of GvHD. CAR-engineered iNKT (CAR-iNKT) cell therapy offers a promising new approach to cancer immunotherapy by overcoming the drawbacks of CAR-T cell therapy while retaining potent antitumor capabilities. This review summarizes the current CAR-iNKT cell products, their functions and phenotypes, and their potential for off-the-shelf cancer immunotherapy.

Keywords:  Invariant natural killer T (iNKT) cell; chimeric antigen receptor (CAR); cancer immunotherapy; tumor microenvironment (TME); genetic engineering; autologous therapy; allogeneic therapy; graft-versus-host disease (GvHD); off-the-shelf cancer therapy

DOI:  https://doi.org/10.2174/0113892010265228231116073012
Cancers (Basel). 2024 Jan 23. pii: 472. [Epub ahead of print]16(3):

The Aryl Hydrocarbon Receptor: Impact on the Tumor Immune Microenvironment and Modulation as a Potential Therapy.

Brian D Griffith, Timothy L Frankel.

  The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear receptor with a broad range of functions, both in tumor cells and immune cells within the tumor microenvironment (TME). Activation of AhR has been shown to have a carcinogenic effect in a variety of organs, through induction of cellular proliferation and migration, promotion of epithelial-to-mesenchymal transition, and inhibition of apoptosis, among other functions. However, the impact on immune cell function is more complicated, with both pro- and anti-tumorigenic roles identified. Although targeting AhR in cancer has shown significant promise in pre-clinical studies, there has been limited efficacy in phase III clinical trials to date. With the contrasting roles of AhR activation on immune cell polarization, understanding the impact of AhR activation on the tumor immune microenvironment is necessary to guide therapies targeting the AhR. This review article summarizes the state of knowledge of AhR activation on the TME, limitations of current findings, and the potential for modulation of the AhR as a cancer therapy.

Keywords:  aryl hydrocarbon receptor; immunotherapy; tumor immune evasion; tumor immune microenvironment

DOI:  https://doi.org/10.3390/cancers16030472
Cell Mol Gastroenterol Hepatol. 2024 Feb 03. pii: S2352-345X(24)00025-0. [Epub ahead of print]

Rethinking the roles of cancer associated fibroblasts in pancreatic cancer.

Ralph Francescone, Howard C Crawford, Debora Barbosa Vendramini-Costa.

Bearing a dismal 5-year survival rate, pancreatic ductal adenocarcinoma (PDAC) is a challenging disease that features a unique fibroinflammatory tumor microenvironment (TME). As major components of the PDAC TME, cancer associated fibroblasts (CAFs) are still poorly understood and their contribution to the several hallmarks of PDAC, such as resistance to therapies, immunosuppression, and high incidence of metastasis, is likely underestimated. There have been encouraging advances in our understanding of these fascinating cells, but many controversies remain, leaving the field still actively exploring the full scope of their contributions in PDAC progression. Here we aim to pose several important considerations regarding PDAC CAF functions. We posit that transcriptomic analyses be interpreted with caution, when aiming to uncover the functional contributions of these cells. Moreover, we propose that normalizing these functions, rather than eliminating them, will provide the opportunity to enhance therapeutic response. Finally, we propose that CAFs should not be studied in isolation, but in conjunction with its extracellular matrix, as their respective functions are coordinated and concordant.

DOI: https://doi.org/10.1016/j.jcmgh.2024.01.022
Int J Biol Sci. 2024 ;20(3): 1110-1124

Fibroblasts: invigorated targets in pre-metastatic niche formation.

Hongkuan Han, Cheng Qian, Mengyao Song, Chongjin Zhong, Yang Zhao, Yin Lu.

  At present, tumor metastasis still remains the leading contributor to high recurrence and mortality in cancer patients. There have been no clinically effective therapeutic strategies for treating patients with metastatic cancer. In recent years, a growing body of evidence has shown that the pre-metastatic niche (PMN) plays a crucial role in driving tumor metastasis. Nevertheless, a clear and detailed understanding of the formation of PMN is still lacking given the fact that PMN formation involves in a wealth of complicated communications and underlying mechanisms between primary tumors and metastatic target organs. Despite that the roles of numerous components including tumor exosomes and extracellular vesicles in influencing the evolution of PMN have been well documented, the involvement of cancer-associated fibroblasts (CAFs) in the tumor microenvironment for controlling PMN formation is frequently overlooked. It has been increasingly recognized that fibroblasts trigger the formation of PMN by virtue of modulating exosomes, metabolism and so on. In this review, we mainly summarize the underlying mechanisms of fibroblasts from diverse origins in exerting impacts on PMN evolution, and further highlight the prospective strategies for targeting fibroblasts to prevent PMN formation.

Keywords:  Cancer-associated fibroblasts; Fibroblast-based therapy; Tumor metastasis; Tumor microenvironment

DOI:  https://doi.org/10.7150/ijbs.87680
Curr Cancer Drug Targets. 2024 Jan 05.

IR-780 Dye-based Targeting of Cancer-associated Fibroblasts Improves Cancer Immunotherapy by Increasing Intra-tumoral T Lymphocytes Infiltration.

Wei Yang, Zelin Chen, Langfan Qu, Can Zhang, Hongdan Chen, Jiancheng Zheng, Wanchao Chen, Xu Tan, Chunmeng Shi.

   BACKGROUND: Immune-checkpoint inhibitors (ICIs) against programmed death (PD)-1/PD-L1 pathway immunotherapy have been demonstrated to be effective in only a subset of patients with cancer, while the rest may exhibit low response or may develop drug resistance after initially responding. Previous studies have indicated that extensive collagen-rich stroma secreted by cancer-associated fibroblasts (CAFs) within the tumor microenvironment is one of the key obstructions of the immunotherapy for some tumors by decreasing the infiltrating cytotoxic T cells. However, there is still a lack of effective therapeutic strategies to control the extracellular matrix by targeting CAFs.
METHODS: The enhanced uptake of IR-780 by CAFs was assessed by using in vivo or ex vivo nearinfrared fluorescence imaging, confocal NIR fluorescent imaging, and CAFs isolation testing. The fibrotic phenotype down-regulation effects and in vitro CAFs killing effect of IR-780 were tested by qPCR, western blot, and flow cytometry. The in vivo therapeutic enhancement of anti-PD-L1 by IR-780 was evaluated on EMT6 and MC38 subcutaneous xenograft mice models.
RESULTS: IR-780 has been demonstrated to be preferentially taken up by CAFs and accumulate in the mitochondria. Further results identified low-dose IR-780 to downregulate the fibrotic phenotype, while high-dose IR-780 could directly kill both CAFs and EMT6 cells in vitro. Moreover, IR-780 significantly inhibited extracellular matrix (ECM) protein deposition in the peri-tumoral stroma on subcutaneous EMT6 and MC38 xenografts, which increased the proportion of tumor-infiltrating lymphocytes (TILs) in the deep tumor and further promoted anti-PD-L1 therapeutic efficacy.
CONCLUSION: This work provides a unique strategy for the inhibition of ECM protein deposition in the tumor microenvironment by targeted regulating of CAFs, which destroys the T cell barrier and further promotes tumor response to PD-L1 monoclonal antibody. IR-780 has been proposed as a potential therapeutic small-molecule adjuvant to promote the effect of immunotherapy.

Keywords:  An-ti-PD-L1; Cancer associated fibroblasts; Extracellular matrix; IR-780; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.2174/0115680096261142231018104854
Diagnostics (Basel). 2024 Feb 02. pii: 328. [Epub ahead of print]14(3):

The Role of Neutrophil Extracellular Traps in the Outcome of Malignant Epitheliomas: Significance of CA215 Involvement.

Mihai Emanuel Himcinschi, Valentina Uscatescu, Georgiana Gherghe, Irina Stoian, Adelina Vlad, Delia Codruța Popa, Daniel Coriu, Andrei Anghel.

  Neutrophil extracellular traps (NETs) were originally discovered as a part of the innate immune response of the host to bacteria. They form a web-like structure that can immobilize microorganisms or exhibit direct antimicrobial properties, such as releasing reactive oxygen species (ROS). NETs are established when neutrophils undergo a sort of cellular death following exposure to ROS, chemokines, cytokines, or other soluble factors. This process results in the release of the neutrophil's DNA in a web-like form, which is decorated with citrullinated histones (H3/H4-cit), neutrophil elastase (NE), and myeloperoxidase (MPO). Emerging studies have put into perspective that NETs play an important role in oncology as they were shown to influence tumor growth, malignant initiation, and proliferation, mediate the transition from endothelial to mesenchymal tissue, stimulate angiogenesis or metastasis, and can even help cancer cells evade the immune response. The role of NETs in cancer therapy resides in their ability to form and act as a mechanical barrier that will provide the primary tumor with a reduced response to irradiation or pharmaceutical penetration. Subsequently, cancer cells are shown to internalize NETs and use them as a strong antioxidant when pharmaceutical treatment is administered. In this review, we explored the role of NETs as part of the tumor microenvironment (TME), in the context of malignant epitheliomas, which are capable of an autonomous production of CA215, a subvariant of IgG, and part of the carcinoembryonic antigen (CEA) superfamily. Studies have shown that CA215 has a functional Fc subdivision able to activate the Fc-gamma-RS receptor on the surface of neutrophils. This activation may afterward stimulate the production of NETs, thus indicating CA215 as a potential factor in cancer therapy surveillance.

Keywords:  CA215; IgG; NETosis; cancer therapy resistance; epithelioma; neutrophil extracellular traps (NETs)

DOI:  https://doi.org/10.3390/diagnostics14030328
Aging (Albany NY). 2024 Feb 07. 16

Comprehensive analysis of ALG3 in pan-cancer and validation of ALG3 as an onco-immunological biomarker in breast cancer.

Xiaolei Xue, Qiaoli Feng, Xi Hong, Zhousheng Lin, Yingrui Luo, Yingshi Li, Guangyu Yao, Nisha Wang, Lujia Chen.

  ALG3 has significant modulatory function in the process of tumor development. Yet how ALG3 involves in the advancement of different malignancies isn't fully understood. We performed a pan-cancer assessment on ALG3 utilizing datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to examine its tumor-related roles across malignancies and its link to particular molecules and cells in the tumor microenvironment (TME). Furthermore, we focused on breast cancer to examine the influence of ALG3-mediated signaling pathways and intercellular interactions in the advancement of tumors. The biological effects of ALG3 were verified by breast cancer cells. Enhanced ALG3 expression was discovered to be substantially linked to patients' grim prognoses in a number of malignancies. Furthermore, the expression of ALG3 in the TME was linked to the infiltration of stromal and immune cells, and ALG3-related immune checkpoints, TMB, and MSI were also discovered. We also discovered that cancer patients having a high level of ALG3 exhibited a lower probability of benefiting from immunotherapy. Furthermore, our research found that KEGG enrichment, single-cell RNA and spatial sequencing analyses were effective in identifying key signaling pathways in ALG3-associated tumor growth. In vitro, knockdown of ALG3 could decrease the proliferation of breast cancer cells. In summary, our research offers a comprehensive insight into the advancement of tumors under the mediation of ALG3. ALG3 appears to be intimately associated with tumor development in the TME. ALG3 might be a viable treatment target for cancer therapy, particularly in the case of breast cancer.

Keywords:  ALG3; TME; biomarker; breast cancer; pan-cancer

DOI:  https://doi.org/10.18632/aging.205483
Methods Mol Biol. 2024 ;2769 153-166

Single-Cell Characterization of the Tumor Ecosystem in Liver Cancer.

Limin Wang, Mahler Revsine, Xin Wei Wang, Lichun Ma.

  Tumor heterogeneity along with the complex landscape of the tumor microenvironment create critical challenges for effective liver cancer interventions. Characterizing the tumor ecosystem at the single-cell level may provide insight into the collective behaviors of tumor cells and their interplays with stromal and immune cells. Here we introduce the experimental protocol and computational methods for the single-cell study of liver cancer, which may be essential for a mechanistic understanding of the tumor ecosystem in liver cancer and further pave the way for developing novel therapeutics.

Keywords:  Biodiversity; Cholangiocarcinoma; Hepatocellular carcinoma; Liver cancer; Single cell; Tumor ecosystem; Tumor heterogeneity; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-1-0716-3694-7_12
Clin Transl Oncol. 2024 Feb 08.

What's new about the tumor microenvironment of urothelial carcinoma?

João Queirós Coelho, Maria João Ramos, Ridhi Ranchor, Rita Pichel, Laura Guerra, Hugo Miranda, Joana Simões, Sérgio Xavier Azevedo, Joana Febra, António Araújo.

  Urothelial carcinoma is a significant global health concern that accounts for a substantial part of cancer diagnoses and deaths worldwide. The tumor microenvironment is a complex ecosystem composed of stromal cells, soluble factors, and altered extracellular matrix, that mutually interact in a highly immunomodulated environment, with a prominent role in tumor development, progression, and treatment resistance. This article reviews the current state of knowledge of the different cell populations that compose the tumor microenvironment of urothelial carcinoma, its main functions, and distinct interactions with other cellular and non-cellular components, molecular alterations and aberrant signaling pathways already identified. It also focuses on the clinical implications of these findings, and its potential to translate into improved quality of life and overall survival. Determining new targets or defining prognostic signatures for urothelial carcinoma is an ongoing challenge that could be accelerated through a deeper understanding of the tumor microenvironment.

Keywords:  Bladder cancer; Immunomodulation; Immunotherapy; Tumor microenvironment; Urothelial cancer

DOI:  https://doi.org/10.1007/s12094-024-03384-w
Nat Cancer. 2024 Feb 08.

PD-L2 expression in senescent cancer cells limits tumor clearance after chemotherapy.

DOI: https://doi.org/10.1038/s43018-023-00713-w
ChemMedChem. 2024 Feb 08. e202300551

Hypoxia: Intriguing Feature in Cancer Cell Biology.

Monalisa Chowdhury, Prasanta Kumar Das.

  Hypoxia, a key aspect of the tumor microenvironment, plays a vital role in cell proliferation, angiogenesis, metabolism, and the immune response within tumors. These factors collectively promote tumor advancement, aggressiveness, metastasis and result in a poor prognosis. Hypoxia inducible factor 1α (HIF-1α), activated under low oxygen conditions, mediates many of these effects by altering drug target expression, metabolic regulation, and oxygen consumption. These changes promote cancer cell growth and survival. Hypoxic tumor cells develop aggressive traits and resistance to chemotherapy and radiotherapy, leading to increased mortality. Targeting hypoxic tumor offers a potential solution to overcome the challenges posed by tumor heterogeneity and can be used in designing diagnostic and therapeutic nanocarriers for various solid cancers. This concept provides an overview of the intricate relationship between hypoxia and the tumor microenvironment, highlighting its potential as a promising tool for cancer therapies. The article explores the development of hypoxia in cancer cells and its role in cancer progression, along with the latest advancements in hypoxia-triggered cancer treatment.

Keywords:  Hypoxia * Cancer * HIF-1α * Hypoxia assisted drug * Nanomaterials

DOI:  https://doi.org/10.1002/cmdc.202300551
Biomed Chromatogr. 2024 Feb 05. e5837

M2 tumor-associated macrophages and CXCL2 induce lipid remodeling in hepatocellular carcinoma cell lines.

Yongling Chen, Ziqing Zhong, Yan Deng, Yu Lu, Xue Qin.

  Primary hepatocellular carcinoma (HCC) is one of the most common malignant tumors, but its pathogenesis remains incompletely elucidated. Recently, many studies indicated that lipid remodeling plays an important role in the occurrence and development of HCC. Furthermore, lipids have been proven to be indispensable mediators in promoting communication between tumor cells and extracellular matrix in the tumor microenvironment. Thus, this study aims to comprehensively investigate the process of lipid remodeling during HCC metastasis based on the LC-electrospray ionization-MS (LC-ESI-MS) combined with multiple reaction monitoring technology. M2 tumor-associated macrophages and the recombinant human protein CXCL2 were used to simulate the tumor microenvironment. After co-incubating SMMC7721 and MHCC97-H cell lines with M2 tumor-associated macrophages or the recombinant human protein CXCL2 for 48 h, LC-ESI-MS was used to quantify the levels of two major classes of lipid molecules, namely, glycerophospholipids and sphingolipids. Our results suggest that lipid remodeling in the tumor microenvironment may promote the migration and invasion of HCC cell lines.

Keywords:  CXCL2; hepatocellular carcinoma; lipid remodeling; tumor-associated macrophages

DOI:  https://doi.org/10.1002/bmc.5837
Br J Pharmacol. 2024 Feb 07.

The impact of Foxp3+ regulatory T-cells on CD8+ T-cell dysfunction in tumour microenvironments and responses to immune checkpoint inhibitors.

Mikhaël Attias, Ciriaco A Piccirillo.

  Immune checkpoint inhibitors (ICIs) have been a breakthrough in cancer therapy, inducing durable remissions in responding patients. However, they are associated with variable outcomes, spanning from disease hyperprogression to complete responses with the onset of immune-related adverse events. The consequences of checkpoint inhibition on Foxp3+ regulatory T (Treg ) cells remain unclear but could provide key insights into these variable outcomes. In this review, we first cover the mechanisms that underlie the development of hot and cold tumour microenvironments, which determine the efficacy of immunotherapy. We then outline how differences in tumour-intrinsic immunogenicity, T-cell trafficking, local metabolic environments and inhibitory checkpoint signalling differentially impair CD8+ T-cell function in tumour microenvironments, all the while promoting Treg -cell suppressive activity. Finally, we focus on the mechanisms that enable the induction of polyfunctional CD8+ T-cells upon checkpoint blockade and discuss the role of ICI-induced Treg -cell reactivation in acquired resistance to treatment.

Keywords:  Foxp3+ Treg-cells; anti-PD-1; checkpoint inhibitors; immune exhaustion; spatial distribution; tumour microenvironment

DOI:  https://doi.org/10.1111/bph.16313
J Leukoc Biol. 2024 Feb 05. pii: qiae027. [Epub ahead of print]

Tissue damage from chronic liver injury inhibits peripheral NK cell abundance and proinflammatory function.

Zonghao You, Shaoxue Ling, Shuwu Zhao, Haixing Han, Yuhong Bian, Yongzhi He, Xi Chen.

  One of the difficulties in the treatment of hepatocellular carcinoma is that it is impossible to eliminate the inhibitory effect of tumor microenvironment on immune response. Therefore, it is particularly important to understand the formation process of tumor microenvironment. Chronic inflammation is the core factor of cancer occurrence and the leading stage of inflammation-cancer transformation, and the NK cell subsets play an important role in it. Our study confirmed that in the stage of chronic liver injury, the local immunosuppressive microenvironment of the liver, that is, the damaged microenvironment, has been formed, but this inhibitory effect is only for peripheral NK cells and has no effect on tissue resident NK subsets. The markers of damage microenvironment are the same as those of tumor microenvironment.

Keywords:  Chronic liver injury; Conventional NK cells; Hepatic carcinoma; Inflammation-cancer transformation; Liver resident NK cells; Tumor microenvironment

DOI:  https://doi.org/10.1093/jleuko/qiae027
FEBS Lett. 2024 Feb 07.

Lipid droplets provide metabolic flexibility for cancer progression.

Rémi Safi, Pablo Menéndez, Albert Pol.

  A hallmark of cancer cells is their remarkable ability to efficiently adapt to favorable and hostile environments. Due to a unique metabolic flexibility, tumor cells can grow even in the absence of extracellular nutrients or in stressful scenarios. To achieve this, cancer cells need large amounts of lipids to build membranes, synthesize lipid-derived molecules, and generate metabolic energy in the absence of other nutrients. Tumor cells potentiate strategies to obtain lipids from other cells, metabolic pathways to synthesize new lipids, and mechanisms for efficient storage, mobilization, and utilization of these lipids. Lipid droplets (LDs) are the organelles that collect and supply lipids in eukaryotes and it is increasingly recognized that the accumulation of LDs is a new hallmark of cancer cells. Furthermore, an active role of LD proteins in processes underlying tumorigenesis has been proposed. Here, by focusing on three major classes of LD-resident proteins (perilipins, lipases, and acyl-CoA synthetases), we provide an overview of the contribution of LDs to cancer progression and discuss the role of LD proteins during the proliferation, invasion, metastasis, apoptosis, and stemness of cancer cells.

Keywords:  cancer; invasion; lipid droplets; lipids; metastasis; tumorigenesis

DOI:  https://doi.org/10.1002/1873-3468.14820