bims-flamet 2024-02-18 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–02–18
28 papers selected by
Peio Azcoaga, Biodonostia HRI

Forces at play: exploring factors affecting the cancer metastasis.
The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy.
Regulation of regulatory T cells and tumor-associated macrophages in gastric cancer tumor microenvironment.
Establishment of immune suppression by cancer cells in the tumor microenvironment.
Protocols for Co-Culture Phenotypic Assays with Breast Cancer Cells and THP-1-Derived Macrophages.
Epigenetic underpinnings of tumor-immune dynamics in prostate cancer immune suppression.
Measuring the composition of the tumor microenvironment with transcriptome analysis: past, present and future.
Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance.
The Role of the Microbiome in the Etiopathogenesis of Colon Cancer.
Using Drosophila to uncover the role of organismal physiology and the tumor microenvironment in cancer.
A review of natural products targeting tumor immune microenvironments for the treatment of lung cancer.
Envision the future of precision medicine in pediatric cancer.
Surgical stress-induced tumor immune suppressive environment.
The paradoxical role of cytokines and chemokines at the tumor microenvironment: a comprehensive review.
EP2 and EP4 blockade prevents tumor-induced suppressive features in human monocytic myeloid-derived suppressor cells.
The role of extracellular vesicles from placenta and endometrium in pregnancy: Insights from tumor biology.
Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target.
Selective targeting or reprogramming of intra-tumoral Tregs.
Exosomes released by oxidative stress-induced mesenchymal stem cells promote murine mammary tumor progression through activating the STAT3 signaling pathway.
Corrigendum: Lipid metabolism and tumor immunotherapy.
Correction: RCAd-LTH-shPD-L1, a double-gene recombinant oncolytic adenovirus with enhanced antitumor immunity, increases lymphocyte infiltration and reshapes the tumor microenvironment.
Interleukin-21 as an adjuvant in cancer immunotherapy: Current advances and future directions.
Acidosis activates breast cancer ferroptosis through ZFAND5/SLC3A2 signaling axis and elicits M1 macrophage polarization.
Cross-talk between disulfidptosis and immune check point genes defines the tumor microenvironment for the prediction of prognosis and immunotherapies in glioblastoma.
Activation of Stimulator of Interferon Genes (STING): Promising Strategy to Overcome Immune Resistance in Prostate Cancer.
Are we getting closer to a successful neoantigen cancer vaccine?
Roles of endothelial cell specific molecule‑1 in tumor angiogenesis (Review).
Bufalin suppresses hepatocellular carcinogenesis by targeting M2 macrophage-governed Wnt1/β-catenin signaling.

Front Immunol. 2024 ;15 1274474

Forces at play: exploring factors affecting the cancer metastasis.

Farooq Riaz, Jing Zhang, Fan Pan.

  Metastatic disease, a leading and lethal indication of deaths associated with tumors, results from the dissemination of metastatic tumor cells from the site of primary origin to a distant organ. Dispersion of metastatic cells during the development of tumors at distant organs leads to failure to comply with conventional treatments, ultimately instigating abrupt tissue homeostasis and organ failure. Increasing evidence indicates that the tumor microenvironment (TME) is a crucial factor in cancer progression and the process of metastatic tumor development at secondary sites. TME comprises several factors contributing to the initiation and progression of the metastatic cascade. Among these, various cell types in TME, such as mesenchymal stem cells (MSCs), lymphatic endothelial cells (LECs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), T cells, and tumor-associated macrophages (TAMs), are significant players participating in cancer metastasis. Besides, various other factors, such as extracellular matrix (ECM), gut microbiota, circadian rhythm, and hypoxia, also shape the TME and impact the metastatic cascade. A thorough understanding of the functions of TME components in tumor progression and metastasis is necessary to discover new therapeutic strategies targeting the metastatic tumor cells and TME. Therefore, we reviewed these pivotal TME components and highlighted the background knowledge on how these cell types and disrupted components of TME influence the metastatic cascade and establish the premetastatic niche. This review will help researchers identify these altered components' molecular patterns and design an optimized, targeted therapy to treat solid tumors and restrict metastatic cascade.

Keywords:  circadian rhythm; extracellular matrix; gut-microbiota; hypoxia; metastasis; metastatic cascade; premetastatic niche; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1274474
Front Immunol. 2024 ;15 1331641

The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy.

Dongming Li, Donghui Cao, Yuanlin Sun, Yingnan Cui, Yangyu Zhang, Jing Jiang, Xueyuan Cao.

  Cancer, a disease that modern medicine has not fully understood and conquered, with its high incidence and mortality, deprives countless patients of health and even life. According to global cancer statistics, there were an estimated 19.3 million new cancer cases and nearly 10 million cancer deaths in 2020, with the age-standardized incidence and mortality rates of 201.0 and 100.7 per 100,000, respectively. Although remarkable advancements have been made in therapeutic strategies recently, the overall prognosis of cancer patients remains not optimistic. Consequently, there are still many severe challenges to be faced and difficult problems to be solved in cancer therapy today. Epigallocatechin gallate (EGCG), a natural polyphenol extracted from tea leaves, has received much attention for its antitumor effects. Accumulating investigations have confirmed that EGCG can inhibit tumorigenesis and progression by triggering apoptosis, suppressing proliferation, invasion, and migration, altering tumor epigenetic modification, and overcoming chemotherapy resistance. Nevertheless, its regulatory roles and biomolecular mechanisms in the immune microenvironment, metabolic microenvironment, and immunotherapy remain obscure. In this article, we summarized the most recent updates about the effects of EGCG on tumor microenvironment (TME), metabolic reprogramming, and anti-cancer immunotherapy. The results demonstrated EGCG can promote the anti-cancer immune response of cytotoxic lymphocytes and dendritic cells (DCs), attenuate the immunosuppression of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and inhibit the tumor-promoting functions of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and various stromal cells including cancer-associated fibroblasts (CAFs), endothelial cells (ECs), stellate cells, and mesenchymal stem/stromal cells (MSCs). Additionally, EGCG can suppress multiple metabolic reprogramming pathways, including glucose uptake, aerobic glycolysis, glutamine metabolism, fatty acid anabolism, and nucleotide synthesis. Finally, EGCG, as an immunomodulator and immune checkpoint blockade, can enhance immunotherapeutic efficacy and may be a promising candidate for antitumor immunotherapy. In conclusion, EGCG plays versatile regulatory roles in TME and metabolic reprogramming, which provides novel insights and combined therapeutic strategies for cancer immunotherapy.

Keywords:  antitumor immunity; epigallocatechin gallate; immunotherapy; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1331641
Cancer Med. 2024 Jan;13(2): e6959

Regulation of regulatory T cells and tumor-associated macrophages in gastric cancer tumor microenvironment.

Zhang Shaopeng, Zheng Yang, Fang Yuan, Huang Chen, Qiu Zhengjun.

   INTRODUCTION: Despite advancements in the methods for prevention and early diagnosis of gastric cancer (GC), GC continues to be the fifth in incidence among major cancers and the third most common cause of cancer-related death. The therapeutic effects of surgery and drug treatment are still unsatisfied and show notable differences according to the tumor microenvironment (TME) of GC.
METHODS: Through screening Pubmed, Embase, and Web of Science, we identified and summarized the content of recent studies that focus on the investigation of Helicobacter pylori (Hp) infection, regulatory T cells (Tregs), and tumor-associated macrophages (TAMs) in the TME of GC. Furthermore, we searched and outlined the clinical research progress of various targeted drugs in GC treatment including CTLA-4, PD-1\PD-L1, and VEGF/VEGFR.
RESULTS: In this review, the findings indicate that Hp infection causes local inflammation and leads to immunosuppressive environment. High Tregs infiltration in the TME of GC is associated with increased induction and recruitment; the exact function of infiltrated Tregs in GC was also affected by phenotypes and immunosuppressive molecules. TAMs promote the development and metastasis of tumors, the induction, recruitment, and function of TAMs in the TME of gastric cancer are also regulated by various factors.
CONCLUSION: Discussing the distinct tumor immune microenvironment (TIME) of GC can deepen our understanding on the mechanism of cancer immune evasion, invasion, and metastasis, help us to reduce the incidence of GC, and guide the innovation of new therapeutic targets for GC eventually.

Keywords:  Hp; TAMs; Tregs; gastric cancer; tumor microenvironment

DOI:  https://doi.org/10.1002/cam4.6959
Proc Jpn Acad Ser B Phys Biol Sci. 2024 ;100(2): 114-122

Establishment of immune suppression by cancer cells in the tumor microenvironment.

Hiroyoshi Nishikawa.

  With the clinical success of immune checkpoint inhibitors (ICIs), cancer immunotherapy has become an important pillar of cancer treatment in various types of cancer. However, more than half of patients fail to respond to ICIs, even in combination, uncovering a limited window of clinical responses. Therefore, it is essential to develop more effective cancer immunotherapies and to define biomarkers for stratifying responders and nonresponders by exploring the immunological landscape in the tumor microenvironment (TME). It has become clear that differences in immune responses in the TME determine the clinical efficacy of cancer immunotherapies. Additionally, gene alterations in cancer cells contribute to the development of the immunological landscape, particularly immune suppression in the TME. Therefore, integrated analyses of immunological and genomic assays are key for understanding diverse immune suppressive mechanisms in the TME. Developing novel strategies to control immune suppression in the TME from the perspective of immunology and the cancer genome is crucial for effective cancer immunotherapy (immune-genome precision medicine).

Keywords:  cancer immunotherapy; immune checkpoint inhibitors; immune suppression; immune-genome precision medicine; tumor microenvironment

DOI:  https://doi.org/10.2183/pjab.100.005
J Mammary Gland Biol Neoplasia. 2024 Feb 10. 29(1): 4

Protocols for Co-Culture Phenotypic Assays with Breast Cancer Cells and THP-1-Derived Macrophages.

Alicja Mazan, Anna A Marusiak.

  Tumor mass comprises not only cancer cells but also heterogeneous populations of immune and stromal cells, along with the components of the extracellular matrix, collectively called the tumor microenvironment (TME). This diverse population of cells can communicate with each other, which can positively or negatively affect tumor growth and progression to malignancy. The most common type of immune cells in the TME are macrophages. Macrophages continuously differentiate into a broad landscape of tumor-associated macrophages (TAMs) in response to numerous signals from the TME, which makes studies on TAMs quite challenging. Therefore, implementing reliable protocols is a milestone for drawing consistent conclusions about the interactions between cancer cells and TAMs. Here, we provide the details for the polarization of a human leukemia monocytic cell line, THP-1, into M0, M1 and M2 macrophages. We also present a step-by-step protocol for a transwell co-culture using a human breast cancer cell line, HCC1806, and THP-1-derived macrophages. Finally, we describe the colony formation and migration assays performed on the breast cancer cells after the co-culture with macrophages to measure the influence of macrophages on the oncogenic features of cancer cells. In summary, our co-culture-based protocols can be a valuable resource for investigating the interactions between macrophages and cancer cells.

Keywords:  Breast cancer; Co-culture; Macrophages; THP-1; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10911-024-09556-2
Trends Cancer. 2024 Feb 09. pii: S2405-8033(24)00004-9. [Epub ahead of print]

Epigenetic underpinnings of tumor-immune dynamics in prostate cancer immune suppression.

Duminduni Hewa Angappulige, Nupam P Mahajan, Kiran Mahajan.

  Prostate cancer (PC) is immunosuppressive and refractory to immunotherapy. Infiltration of myeloid-derived suppressor cells (MDSCs) and senescent-like neutrophils and T cell exhaustion are observed in the tumor microenvironment (TME) following androgen receptor (AR) antagonism with antiandrogens or androgen ablation. De novo post-translational acetylation of the AR, HOXB13, and H2A at K609, K13, and K130, respectively, and phosphorylation of H4 at Y88 have emerged as key epigenetic modifications associated with castration-resistant PC (CRPC). The resulting chromatin changes are integrated into cellular processes via phosphorylation of the AR, ACK1, ATPF1A, and SREBP1 at Y267, Y284, Y243/Y246, and Y673/Y951, respectively. In this review, we discuss how these de novo epigenetic alterations drive resistance and how efforts aimed at targeting these regulators may overcome immune suppression observed in PC.

Keywords:  chromatin; epigenetics; immune suppression; prostate cancer; testosterone

DOI:  https://doi.org/10.1016/j.trecan.2024.01.004
Future Oncol. 2024 Feb 16.

Measuring the composition of the tumor microenvironment with transcriptome analysis: past, present and future.

Han Zhang, Xinghua Lu, Binfeng Lu, Giuseppe Gullo, Lujia Chen.

  Interactions between tumor cells and immune cells in the tumor microenvironment (TME) play a vital role the mechanisms of immune evasion, by which cancer cells escape immune elimination. Thus, the characterization and quantification of different components in the TME is a hot topic in molecular biology and drug discovery. Since the development of transcriptome sequencing in bulk tissue, single cells and spatial dimensions, there are increasing methods emerging to deconvolute and subtype the TME. This review discusses and compares such computational strategies and downstream subtyping analyses. Integrative analyses of the transcriptome with other data, such as epigenetics and T-cell receptor sequencing, are needed to obtain comprehensive knowledge of the dynamic TME.

Keywords:  TME subtype; bulk-RNAseq; cell-cell network; deconvolution; immune phenotype; immunotherapy; scRNAseq; spatial transcriptome; tumor microenvironment

DOI:  https://doi.org/10.2217/fon-2023-0658
NPJ Precis Oncol. 2024 Feb 10. 8(1): 31

Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance.

Shujing Wang, Jingrui Wang, Zhiqiang Chen, Jiamin Luo, Wei Guo, Lingling Sun, Lizhu Lin.

Tumor drug resistance emerges from the interaction of two critical factors: tumor cellular heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) constitute essential components of the TME. M2-like TAMs are essential in facilitating tumor metastasis as well as augmenting the drug resistance of tumors. This review encapsulates the mechanisms that M2-like TAMs use to promote tumor drug resistance. We also describe the emerging therapeutic strategies that are currently targeting M2-like TAMs in combination with other antitumor drugs, with some still undergoing clinical trial evaluation. Furthermore, we summarize and analyze various existing approaches for developing novel drugs that target M2-like TAMs to overcome tumor resistance, highlighting how targeting M2-like TAMs can effectively stop tumor growth, metastasis, and overcome tumor drug resistance.

DOI: https://doi.org/10.1038/s41698-024-00522-z
Annu Rev Physiol. 2024 Feb 12. 86 453-478

The Role of the Microbiome in the Etiopathogenesis of Colon Cancer.

Geniver El Tekle, Natalia Andreeva, Wendy S Garrett.

  Studies in preclinical models support that the gut microbiota play a critical role in the development and progression of colorectal cancer (CRC). Specific microbial species and their corresponding virulence factors or associated small molecules can contribute to CRC development and progression either via direct effects on the neoplastic transformation of epithelial cells or through interactions with the host immune system. Induction of DNA damage, activation of Wnt/β-catenin and NF-κB proinflammatory pathways, and alteration of the nutrient's availability and the metabolic activity of cancer cells are the main mechanisms by which the microbiota contribute to CRC. Within the tumor microenvironment, the gut microbiota alter the recruitment, activation, and function of various immune cells, such as T cells, macrophages, and dendritic cells. Additionally, the microbiota shape the function and composition of cancer-associated fibroblasts and extracellular matrix components, fashioning an immunosuppressive and pro-tumorigenic niche for CRC. Understanding the complex interplay between gut microbiota and tumorigenesis can provide therapeutic opportunities for the prevention and treatment of CRC.

Keywords:  cancer immunity; colorectal cancer; metabolism; microbiome; neoplastic transformation; tumor microenvironment

DOI:  https://doi.org/10.1146/annurev-physiol-042022-025619
Trends Cancer. 2024 Feb 13. pii: S2405-8033(24)00007-4. [Epub ahead of print]

Using Drosophila to uncover the role of organismal physiology and the tumor microenvironment in cancer.

Chaitali Khan, Nasser M Rusan.

  Cancer metastasis causes over 90% of cancer patient fatalities. Poor prognosis is determined by tumor type, the tumor microenvironment (TME), organ-specific biology, and animal physiology. While model organisms do not fully mimic the complexity of humans, many processes can be studied efficiently owing to the ease of genetic, developmental, and cell biology studies. For decades, Drosophila has been instrumental in identifying basic mechanisms controlling tumor growth and metastasis. The ability to generate clonal populations of distinct genotypes in otherwise wild-type animals makes Drosophila a powerful system to study tumor-host interactions at the local and global scales. This review discusses advancements in tumor biology, highlighting the strength of Drosophila for modeling TMEs and systemic responses in driving tumor progression and metastasis.

Keywords:  Drosophila; cancer; inflammation; metabolism; metastasis; organ-specific response; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2024.01.007
Front Immunol. 2024 ;15 1343316

A review of natural products targeting tumor immune microenvironments for the treatment of lung cancer.

Pengyu Yao, Su Liang, Zhenying Liu, Cuiping Xu.

  Lung cancer (LC) produces some of the most malignant tumors in the world, with high morbidity and mortality. Tumor immune microenvironment (TIME), a component of the tumor microenvironment (TME), are critical in tumor development, immune escape, and drug resistance. The TIME is composed of various immune cells, immune cytokines, etc, which are important biological characteristics and determinants of tumor progression and outcomes. In this paper, we reviewed the recently published literature and discussed the potential uses of natural products in regulating TIME. We observed that a total of 37 natural compounds have been reported to exert anti-cancer effects by targeting the TIME. In different classes of natural products, terpenoids are the most frequently mentioned compounds. TAMs are one of the most investigated immune cells about therapies with natural products in TIME, with 9 natural products acting through it. 17 natural products exhibit anti-cancer properties in LC by modulating PD-1 and PD-L1 protein activity. These natural products have been extensively evaluated in animal and cellular LC models, but their clinical trials in LC patients are lacking. Based on the current review, we have revealed that the mechanisms of LC can be treated with natural products through TIME intervention, resulting in a new perspective and potential therapeutic drugs.

Keywords:  immune cells; immune cytokines; lung cancer; natural compounds; review; tumor immune microenvironments

DOI:  https://doi.org/10.3389/fimmu.2024.1343316
Cancer Cell. 2024 Feb 12. pii: S1535-6108(24)00011-4. [Epub ahead of print]42(2): 177-179

Envision the future of precision medicine in pediatric cancer.

Y A DeClerck.

Exploring the diversity within the tumor microenvironment (TME) can offer crucial insights to steer cancer therapy toward precision medicine. In this issue of Cancer Cell, Wienke et al. undertake a comprehensive single-cell analysis of neuroblastoma, unveiling its immune landscape and identifying NECTIN2-TIGIT as a promising target for immunotherapy.

DOI: https://doi.org/10.1016/j.ccell.2024.01.006
Carcinogenesis. 2024 Feb 15. pii: bgae012. [Epub ahead of print]

Surgical stress-induced tumor immune suppressive environment.

Fan Yang, Qing Hua, Xiaoyan Zhu, Pingbo Xu.

  Despite significant advances in cancer treatment over the decades, surgical resection remains a prominent management approach for solid neoplasms. Unfortunately, accumulating evidence suggests that surgical stress caused by tumor resection may potentially trigger postoperative metastatic niche formation. Surgical stress not only activates the sympathetic-adrenomedullary axis and hypothalamic-pituitary-adrenocortical axis but also induces a hypoxia and hypercoagulable state. These adverse factors can negatively impact the immune system by downregulating immune effector cells and upregulating immune suppressor cells, which contribute to the colonization and progression of postoperative tumor metastatic niche. This review summarizes the effects of surgical stress on four types of immune effector cells (neutrophils, macrophages, natural killer cells, and cytotoxic T lymphocytes) and two types of immunosuppressive cells (regulatory T cells and myeloid-derived suppressor cells), and discusses the immune mechanisms of postoperative tumor relapse and progression. Additionally, relevant therapeutic strategies to minimize the pro-tumorigenic effects of surgical stress are elucidated.

Keywords:  microenvironment; postoperative immunosuppression; surgical stress; tumor relapse

DOI:  https://doi.org/10.1093/carcin/bgae012
Eur J Med Res. 2024 Feb 15. 29(1): 124

The paradoxical role of cytokines and chemokines at the tumor microenvironment: a comprehensive review.

Toufik Abdul-Rahman, Shankhaneel Ghosh, Sarah M Badar, Abubakar Nazir, Gafar Babatunde Bamigbade, Narjiss Aji, Poulami Roy, Hajar Kachani, Neil Garg, Lukman Lawal, Zarah Sophia Blake Bliss, Andrew Awuah Wireko, Oday Atallah, Favour Tope Adebusoye, Tetiana Teslyk, Kateryna Sikora, Viktoriia Horbas.

  Tumor progression and eradication have long piqued the scientific community's interest. Recent discoveries about the role of chemokines and cytokines in these processes have fueled renewed interest in related research. These roles are frequently viewed as contentious due to their ability to both suppress and promote cancer progression. As a result, this review critically appraised existing literature to discuss the unique roles of cytokines and chemokines in the tumor microenvironment, as well as the existing challenges and future opportunities for exploiting these roles to develop novel and targeted treatments. While these modulatory molecules play an important role in tumor suppression via enhanced cancer-cell identification by cytotoxic effector cells and directly recruiting immunological effector cells and stromal cells in the TME, we observed that they also promote tumor proliferation. Many cytokines, including GM-CSF, IL-7, IL-12, IL-15, IL-18, and IL-21, have entered clinical trials for people with advanced cancer, while the FDA has approved interferon-alpha and IL-2. Nonetheless, low efficacy and dose-limiting toxicity limit these agents' full potential. Conversely, Chemokines have tremendous potential for increasing cancer immune-cell penetration of the tumor microenvironment and promoting beneficial immunological interactions. When chemokines are combined with cytokines, they activate lymphocytes, producing IL-2, CD80, and IL-12, all of which have a strong anticancer effect. This phenomenon opens the door to the development of effective anticancer combination therapies, such as therapies that can reverse cancer escape, and chemotaxis of immunosuppressive cells like Tregs, MDSCs, and TAMs.

Keywords:  Cancer; Chemokines; Cytokines; Tumor; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40001-024-01711-z
Front Immunol. 2024 ;15 1355769

EP2 and EP4 blockade prevents tumor-induced suppressive features in human monocytic myeloid-derived suppressor cells.

Jorge Cuenca-Escalona, Beatriz Subtil, Alba Garcia-Perez, Alessandra Cambi, I Jolanda M de Vries, Georgina Flórez-Grau.

  Tumors educate their environment to prime the occurrence of suppressive cell subsets, which enable tumor evasion and favors tumor progression. Among these, there are the myeloid-derived suppressor cells (MDSCs), their presence being associated with the poor clinical outcome of cancer patients. Tumor-derived prostaglandin E2 (PGE2) is known to mediate MDSC differentiation and the acquisition of pro-tumor features. In myeloid cells, PGE2 signaling is mediated via E-prostanoid receptor type 2 (EP2) and EP4. Although the suppressive role of PGE2 is well established in MDSCs, the role of EP2/4 on human MDSCs or whether EP2/4 modulation can prevent MDSCs suppressive features upon exposure to tumor-derived PGE2 is poorly defined. In this study, using an in vitro model of human monocytic-MDSCs (M-MDSCs) we demonstrate that EP2 and EP4 signaling contribute to the induction of a pro-tumor phenotype and function on M-MDSCs. PGE2 signaling via EP2 and EP4 boosted M-MDSC ability to suppress T and NK cell responses. Combined EP2/4 blockade on M-MDSCs during PGE2 exposure prevented the occurrence of these suppressive features. Additionally, EP2/4 blockade attenuated the suppressive phenotype of M-MDSCs in a 3D coculture with colorectal cancer patient-derived organoids. Together, these results identify the role of tumor-derived PGE2 signaling via EP2 and EP4 in this human M-MDSC model, supporting the therapeutic value of targeting PGE2-EP2/4 axis in M-MDSCs to alleviate immunosuppression and facilitate the development of anti-tumor immunity.

Keywords:  E-prostanoid receptor type 2; E-prostanoid receptor type 4; M-MDSCs; prostaglandin E2; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1355769
J Reprod Immunol. 2024 Feb 01. pii: S0165-0378(24)00019-6. [Epub ahead of print]162 104210

The role of extracellular vesicles from placenta and endometrium in pregnancy: Insights from tumor biology.

Yanjun Wang, Songchen Cai, Xian Chen, Qing Sun, Tailang Yin, Lianghui Diao.

  Extracellular vesicles (EVs) are small membrane-bound particles secreted by various cell types that play a critical role in intercellular communication by packaging and delivering biomolecules. In recent years, EVs have emerged as essential messengers in mediating physiological and pathological processes in tumor biology. The tumor microenvironment (TME) plays a pivotal role in tumor generation, progression, and metastasis. In this review, we provide an overview of the impact of tumor-derived EVs on both tumor cells and the TME. Moreover, we draw parallels between tumor biology and pregnancy, as successful embryo implantation also requires intricate intercellular communication between the placental trophecepiblast and the endometrial epithelium. Additionally, we discuss the involvement of EVs in targeting immune responses, trophoblast invasion, migration, and angiogenesis, which are shared biological processes between tumors and pregnancy. Specifically, we highlight the effects of placenta-derived EVs on the fetal-maternal interface, placenta, endometrium, and maternal system, as well as the role of endometrium-derived EVs in embryo-endometrial communication. However, challenges still exist in EVs research, including the standardization of EVs isolation methods for diagnostic testing, which also apply to reproductive systems where EVs-mediated communication is proposed to take place. Through this review, we aim to deepen the understanding of EVs, particularly in the context of reproductive biology, and encourage further investigation in this field.

Keywords:  Assisted Reproductive Technique; Endometrium; Extracellular Vesicles; Placenta; Tumor Microenvironment

DOI:  https://doi.org/10.1016/j.jri.2024.104210
Front Immunol. 2024 ;15 1287459

Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target.

Conner Hartupee, Bolni Marius Nagalo, Chiswili Y Chabu, Mulu Z Tesfay, Joycelynn Coleman-Barnett, John T West, Omeed Moaven.

  Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and treatment barriers contribute to the lack of substantial success in the treatment of this challenging-to-treat malignancy. Desmoplasia is the hallmark of PDAC microenvironment that creates a physical and immunologic barrier. Stromal support cells and immunomodulatory cells face aberrant signaling by pancreatic cancer cells that shifts the complex balance of proper repair mechanisms into a state of dysregulation. The product of this dysregulation is the desmoplastic environment that encases the malignant cells leading to a dense, hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance, and suppresses anti-tumor immune invasion. This desmoplastic environment combined with the immunoregulatory events that allow it to persist serve as the primary focus of this review. The physical barrier and immune counterbalance in the tumor microenvironment (TME) make PDAC an immunologically cold tumor. To convert PDAC into an immunologically hot tumor, tumor microenvironment could be considered alongside the tumor cells. We discuss the complex network of microenvironment molecular and cellular composition and explore how they can be targeted to overcome immuno-therapeutic challenges.

Keywords:  PDAC TME; cancer immunology; immune therapeutics; pancreatic adenocarcinoma; tumor immune microenvironment; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1287459
Med Oncol. 2024 Feb 11. 41(3): 71

Selective targeting or reprogramming of intra-tumoral Tregs.

Keywan Mortezaee.

  Regulatory T cells (Tregs) are critical immunosuppressive cells that are frequently present in the tumor microenvironment of solid cancers and enable progression of tumors toward metastasis. The cells expand in response to tumor-associated antigens and are actively involved in bypassing immunotherapy with immune checkpoint inhibitors through integrating numerous environmental signals. A point here is that Tregs are clonally distinct in peripheral blood from tumor area. Currently, an effective and novel task in cancer immunotherapy is to selectively destabilize or deplete intra-tumoral Tregs in order to avoid systemic inflammatory events. Helios is a transcription factor expressed selectively by Tregs and promotes their stabilization, and Trps1 is a master regulator of intra-tumoral Tregs. Anti-CCR8 and the IL-2Rβγ agonist Bempegaldesleukin selectively target intra-tumoral Treg population, with the former approved to not elicit autoimmunity. Disarming Treg-related immunosuppression in tumors through diverting their reprogramming or promoting naïve T cell differentiation into cells with effector immune activating profile is another promising area of research in cancer immunotherapy. Blimp-1 inhibitors and glucocorticoid-induced TNFR-related protein agonists are example approaches that can be used for diverting Treg differentiation into Th1-like CD4+ T cells, thereby powering immunogenicity against cancer. Finally, selective target of intra-tumoral Tregs and their reprogramming into effector T cells is applicable using low-dose chemotherapy, and high-salt and high-tryptophan diet.

Keywords:  B lymphocyte-induced maturation protein (Blimp); Helios; IL-2; Immunotherapy; Regulatory T cell (Treg); Reprogramming; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1007/s12032-024-02300-0
Mol Cell Biochem. 2024 Feb 13.

Exosomes released by oxidative stress-induced mesenchymal stem cells promote murine mammary tumor progression through activating the STAT3 signaling pathway.

Mansour Almouh, Katayoon Pakravan, Mohammad H Ghazimoradi, Romina Motamed, Babak Bakhshinejad, Zuhair Mohammad Hassan, Sadegh Babashah.

  Mesenchymal stem cells (MSCs) may play a pivotal role in shaping the tumor microenvironment (TME), influencing tumor growth. Nonetheless, conflicting evidence exists regarding the distinct impacts of MSCs on tumor progression, with some studies suggesting promotion while others indicate suppression of tumor cell growth. Considering that oxidative stress is implicated in the dynamic interaction between components of the TME and tumor cells, we investigated the contribution of exosomes released by hydrogen peroxide (H2O2)-treated MSCs to murine mammary tumor growth and progression. Additionally, we aimed to identify the underlying mechanism through which MSC-derived exosomes affect breast tumor growth and angiogenesis. Our findings demonstrated that exosomes released by H2O2-treated, stress-induced MSCs (St-MSC Exo) promoted breast cancer cell progression by inducing the expression of vascular endothelial growth factor (VEGF) and markers associated with epithelial-to-mesenchymal transition. Further clarification revealed that the promoting effect of St-MSC Exo on VEGF expression may, in part, depend on activating STAT3 signaling in BC cells. In contrast, exosomes derived from untreated MSCs retarded JAK1/STAT3 phosphorylation and reduced VEGF expression. Additionally, our observations revealed that the activation of the transcription factor NF-κB in BC cells, stimulated with St-MSC Exo, occurs concurrently with an increase in intracellular ROS production. Moreover, we observed that the increase in VEGF secretion into the conditioned media of 4T1 BC, mediated by St-MSC Exo, positively influenced endothelial cell proliferation, migration, and vascular behavior in vitro. In turn, our in vivo studies confirmed that St-MSC Exo, but not exosomes derived from untreated MSCs, exhibited a significant promoting effect on breast tumorigenicity. Collectively, our findings provide new insights into how MSCs may contribute to modulating the TME. We propose a novel mechanism through which exosomes derived from oxidative stress-induced MSCs may contribute to tumor progression and angiogenesis.

Keywords:  Breast cancer; Exosomes; Mesenchymal stem cells; Oxidative stress; STAT3 signaling; Vascular endothelial growth factor

DOI:  https://doi.org/10.1007/s11010-024-04934-0
Front Cell Dev Biol. 2024 ;12 1349379

Corrigendum: Lipid metabolism and tumor immunotherapy.

Yue Wang, Zongjin Guo, Adamu Danbala Isah, Shuangwei Chen, Yongfei Ren, Huazhong Cai.

  [This corrects the article DOI: 10.3389/fcell.2023.1187989.].

Keywords:  combination therapy; immune cells; immunotherapy; lipid metabolism; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2024.1349379
J Immunother Cancer. 2024 Feb 15. pii: e007171corr2. [Epub ahead of print]12(2):

Correction: RCAd-LTH-shPD-L1, a double-gene recombinant oncolytic adenovirus with enhanced antitumor immunity, increases lymphocyte infiltration and reshapes the tumor microenvironment.

DOI: https://doi.org/10.1136/jitc-2023-007171corr2
Biochim Biophys Acta Rev Cancer. 2024 Feb 12. pii: S0304-419X(24)00015-5. [Epub ahead of print] 189084

Interleukin-21 as an adjuvant in cancer immunotherapy: Current advances and future directions.

Xinyang Li, Meng Wu, Jie Lu, Jinming Yu, Dawei Chen.

  Immunotherapy has revolutionized cancer treatment. However, it's well-recognized that a considerable proportion of patients fail to benefit from immunotherapy, and to improve immunotherapy response is clinically urgent. Insufficient immune infiltration and immunosuppressive tumor microenvironments (TME) are main contributors to immunotherapy resistance. Thus sustaining functional self-renewal capacity for immune cells and subverting immune-suppressive signals are potential strategies for boosting the efficacy of immunotherapy. Interleukin-21 (IL-21), a crucial cytokine, which could enhance cytotoxic function of immune cells and reduces immunosuppressive cells enrichment in TME, shows promising orientations as an immunoadjuvant in tumor immunotherapy. This review focuses on IL-21 in cancer treatment, including function and mechanisms of IL-21, preclinical and clinical studies, and future directions for IL-21-assisted therapies.

Keywords:  IL-21; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2024.189084
Cancer Lett. 2024 Feb 13. pii: S0304-3835(24)00125-3. [Epub ahead of print] 216732

Acidosis activates breast cancer ferroptosis through ZFAND5/SLC3A2 signaling axis and elicits M1 macrophage polarization.

Hanchu Xiong, Yanan Zhai, Yimei Meng, Zhuazhua Wu, Anchen Qiu, Yu Cai, Geyi Wang, Liu Yang.

  Acidosis is involved in multiple pathways in tumor cells and immune cells among the tumor microenvironment (TME). Ferroptosis is a nonapoptotic and iron-dependent form of cell death characterized by accumulation of lipid peroxidation involved in various cancers. The role of ferroptosis in the breast cancer (BC) acidic microenvironment remains unrevealed. Here, we reported that short-term acidosis induced ferroptosis of BC cells in the zinc finger AN1-type domain 5 (ZFAND5)/solute carrier family 3 member 2 (SLC3A2) dependent manner to suppress tumor growth using in silico and multiple biological methods. Mechanistically, we demonstrated that short-term acidosis increased total/lipid reactive oxygen species (ROS) level, decreased glutathione (GSH) level and induced the morphological changes of mitochondria. Specifically, acidosis restrained the protein stability of SLC3A2 by promoting its ubiquitination process. The prognostic analysis showed that higher expression of ZFAND5 and lower expression of SLC3A2 were correlated with longer overall survival of BC patient, respectively. Furthermore, in combination with ferroptosis agonist metformin, short-term acidosis could synergistically inhibit viability and enhance the ferroptosis of BC cells. Meanwhile, by the exploration of immune cells, short-term acidosis also induced M1 macrophage polarization, triggering processes of phagocytosis and ferroptosis in BC cells. This study demonstrated that short-term acidosis induced BC cell ferroptosis through ZFAND5/SLC3A2 signaling axis and promoted phagocytosis and ferroptosis of BC cells with M1 macrophage polarization, which might be a new mechanism for BC therapy.

Keywords:  Acidosis; Breast cancer; Ferroptosis; Macrophage; Metformin; Ubiquitination

DOI:  https://doi.org/10.1016/j.canlet.2024.216732
Sci Rep. 2024 Feb 16. 14(1): 3901

Cross-talk between disulfidptosis and immune check point genes defines the tumor microenvironment for the prediction of prognosis and immunotherapies in glioblastoma.

Yanjun Zhou, Xue Qin, Qunchao Hu, Shaolei Qin, Ran Xu, Ke Gu, Hua Lu.

Disulfidptosis is a condition where dysregulated NAPDH levels and abnormal accumulation of cystine and other disulfides occur in cells with high SLC7A11 expression under glucose deficiency. This disrupts normal formation of disulfide bonds among cytoskeletal proteins, leading to histone skeleton collapse and triggering cellular apoptosis. However, the correlation between disulfidptosis and immune responses in relation to glioblastoma survival rates and immunotherapy sensitivity remains understudied. Therefore, we utilized The Cancer Genome Atlas and The Chinese Glioma Genome Atlas to identify disulfidptosis-related immune checkpoint genes and established an overall survival (OS) prediction model comprising six genes: CD276, TNFRSF 14, TNFSF14, TNFSF4, CD40, and TNFRSF18, which could also be used for predicting immunotherapy sensitivity. We identified a cohort of glioblastoma patients classified as high-risk, which exhibited an upregulation of angiogenesis, extracellular matrix remodeling, and epithelial-mesenchymal transition as well as an immunosuppressive tumor microenvironment (TME) enriched with tumor associated macrophages, tumor associated neutrophils, CD8 + T-cell exhaustion. Immunohistochemical staining of CD276 in 144 cases further validated its negative correlation with OS in glioma. Disulfidptosis has the potential to induce chronic inflammation and an immunosuppressive TME in glioblastoma.

DOI: https://doi.org/10.1038/s41598-024-52128-x
Curr Med Chem. 2024 Feb 12.

Activation of Stimulator of Interferon Genes (STING): Promising Strategy to Overcome Immune Resistance in Prostate Cancer.

Mohammed Alnukhali, Omar Altabbakh, Ammad Ahmad Farooqi, Alan Pollack, Sylvia Daunert, Sapna Deo, Wensi Tao.

  Prostate cancer (PCa) is the most frequent and second-lethal cancer among men. Despite considerable efforts to explore treatments like autologous cellular immunotherapy and immune checkpoint inhibitors, their success remains limited. The intricate tumor microenvironment (TME) and its interaction with the immune system pose significant challenges in PCa treatment. Consequently, researchers have directed their focus on augmenting the immune system's anti-tumor response by targeting the STimulator of the Interferon Genes (STING) pathway. The STING pathway is activated when foreign DNA is detected in the cytoplasm of innate immune cells, resulting in the activation of endoplasmic reticulum (ER) STING. This, in turn, triggers an augmentation of signaling, leading to the production of type I interferon (IFN) and other pro-inflammatory cytokines. Numerous studies have demonstrated that activation of the STING pathway induces immune system rejection and targeted elimination of PCa cells. Researchers have been exploring various methods to activate the STING pathway, including the use of bacterial vectors to deliver STING agonists and the combination of radiation therapy with STING agonists. Achieving effective radiation therapy with minimal side effects and optimal anti-tumor immune responses necessitates precise adjustments to radiation dosing and fractionation schedules. This comprehensive review discusses promising findings from studies focusing on activating the STING pathway to combat PCa. The STING pathway exhibits the potential to serve as an effective treatment modality for PCa, offering new hope for improving the lives of those affected by this devastating disease.

Keywords:  STING pathway; cGAS-STING; disease.; immune resistance; prostate cancer; radiotherapy

DOI:  https://doi.org/10.2174/0109298673273303231208071403
Mol Aspects Med. 2024 Feb 13. pii: S0098-2997(24)00013-X. [Epub ahead of print]96 101254

Are we getting closer to a successful neoantigen cancer vaccine?

Karen Manoutcharian, Goar Gevorkian.

  Although significant advances in immunotherapy have revolutionized the treatment of many cancer types over the past decade, the field of vaccine therapy, an important component of cancer immunotherapy, despite decades-long intense efforts, is still transmitting signals of promises and awaiting strong data on efficacy to proceed with regulatory approval. The field of cancer vaccines faces standard challenges, such as tumor-induced immunosuppression, immune response in inhibitory tumor microenvironment (TME), intratumor heterogeneity (ITH), permanently evolving cancer mutational landscape leading to neoantigens, and less known obstacles: neoantigen gain/loss upon immunotherapy, the timing and speed of appearance of neoantigens and responding T cell clonotypes and possible involvement of immune interference/heterologous immunity, in the complex interplay between evolving tumor epitopes and the immune system. In this review, we discuss some key issues related to challenges hampering the development of cancer vaccines, along with the current approaches focusing on neoantigens. We summarize currently well-known ideas/rationales, thus revealing the need for alternative vaccine approaches. Such a discussion should stimulate vaccine researchers to apply out-of-box, unconventional thinking in search of new avenues to deal with critical, often yet unaddressed challenges on the road to a new generation of therapeutics and vaccines.

Keywords:  Cancer immunotherapy; Cancer vaccine; Inhibitory tumor microenvironment (TME); Intratumor heterogeneity (ITH); Neoantigen

DOI:  https://doi.org/10.1016/j.mam.2024.101254
Oncol Lett. 2024 Mar;27(3): 137

Roles of endothelial cell specific molecule‑1 in tumor angiogenesis (Review).

Jie Zhou, Ping Zhou, Jinfang Wang, Jie Song.

  Angiogenesis plays a crucial role in tumor growth and metastasis, and is heavily influenced by the tumor microenvironment (TME). Endothelial cell dysfunction is a key factor in tumor angiogenesis and is characterized by the aberrant expression of pro-angiogenic factors. Endothelial cell specific molecule-1 (ESM1), also known as endocan, is a marker of endothelial cell dysfunction. Although ESM1 is primarily expressed in normal endothelial cells, dysregulated ESM1 expression has been observed in human tumors and animal tumor models, and implicated in tumor growth, metastasis and angiogenesis. The precise role of ESM1 in tumor angiogenesis and its potential regulatory mechanisms are not yet conclusively defined. However, the aim of the present review was to explore the involvement of ESM1 in the process of tumor angiogenesis in the TME and the characteristics of neovascularization. In addition, the present review discusses the interaction between ESM1 and angiogenic factors, as well as the mechanisms through which ESM1 contributes to tumor angiogenesis. Furthermore, the reciprocal regulation between ESM1 and the TME is explored. Finally, the potential of targeting ESM1 as a therapeutic strategy for tumor angiogenesis is presented.

Keywords:  endocan; endothelial cell specific molecule-1; hypoxia; inflammation; tumor angiogenesis; tumor microenvironment

DOI:  https://doi.org/10.3892/ol.2024.14270
Phytomedicine. 2024 Jan 30. pii: S0944-7113(24)00060-6. [Epub ahead of print]126 155395

Bufalin suppresses hepatocellular carcinogenesis by targeting M2 macrophage-governed Wnt1/β-catenin signaling.

Xuemei Zhang, Xiaona Lu, Jia Shi, Yuyao Li, Yue Li, Ru Tao, Lingying Huang, Yifei Tang, Xiaojun Zhu, Man Li, Yueqiu Gao, Hai Feng, Zhuo Yu.

   BACKGROUND: The interplay of tumor-associated macrophages (TAMs) and tumor cells plays a key role in the development of hepatocellular carcinoma (HCC) and provides an important target for HCC therapy. The communication between them is still on the investigation. Bufalin, the active component derived from the traditional Chinese medicine (TCM) Chansu, has been evidenced to possess anti-HCC activity by directly suppressing tumor cells, while its immunomodulatory effect on the tumor microenvironment (TME) is unclear.
PURPOSE: To explore the mechanism of M2 TAM-governed tumor cell proliferation and the inhibitory effect of bufalin on HCC growth by targeting M2 macrophages.
METHODS: Morphology and marker proteins were detected to evaluate macrophage polarization via microscopy and flow cytometry. Cellular proliferation and malignant transformation of HCC cells cultured with macrophage conditioned medium (CM) or bufalin-primed M2-CM, were assessed by cell viability, colony formation and soft agar assays. Regulations of gene transcription and protein expression and release were determined by RT-qPCR, immunoblotting, immunoprecipitation, ELISA and immunofluorescence. Tumorigenicity upon bufalin treatment was verified in orthotopic and diethylnitrosamine-induced HCC mouse model.
RESULTS: In this study, we first verified that M2 macrophages secreted Wnt1, which acted as a mediator to trigger β-catenin activation in HCC cells, leading to cellular proliferation. Bufalin suppressed HCC cell proliferation and malignant transformation by inhibiting Wnt1 release in M2 macrophages, and dose-dependently inhibited HCC progression in mice. Mechanistically, bufalin specially targeted to block Wnt1 transcription, thus inactivating β-catenin signaling cascade in HCC cells and leading to tumor regression in HCC mouse model.
CONCLUSION: These results clearly reveal a novel potential of bufalin to suppress HCC through immunomodulation, and shed light on a new M2 macrophage-based modality of HCC immunotherapy, which additively enhances direct tumor-inhibitory efficacy of bufalin.

Keywords:  Bufalin; Hepatocellular carcinoma; M2 macrophage; Wnt1; β-catenin signaling

DOI:  https://doi.org/10.1016/j.phymed.2024.155395