bims-flamet 2024-12-01 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–12–01
25 papers selected by
Peio Azcoaga, Biodonostia HRI

Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.
The complex role of regulatory cells in breast cancer: implication for immunopathogenesis and immunotherapy.
Natural products: promising therapeutics for targeting regulatory immune cells in the tumor microenvironment.
Ferroptosis and the tumor microenvironment.
Harnessing Bacterial Agents to Modulate the Tumor Microenvironment and Enhance Cancer Immunotherapy.
Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy.
Targeting extracellular matrix interaction in gastrointestinal cancer: Immune modulation, metabolic reprogramming, and therapeutic strategies.
Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication.
Tumor microenvironment and cancer metastasis: molecular mechanisms and therapeutic implications.
Progression of the Immune Escape Mechanism in Tumors.
Understanding the role of TNFR2 signaling in the tumor microenvironment of breast cancer.
Q&A with Ilaria Elia.
Q&A with Ping Gao.
Exosomal circular RNAs in tumor microenvironment: An emphasis on signaling pathways and clinical opportunities.
Boosting antitumor immunity in breast cancers: Potential of adjuvants, drugs, and nanocarriers.
The Clinical Significance of Cancer-Associated Fibroblasts Classification in Non-Small Cell Lung Cancer.
CAR-armored-cell therapy in solid tumor treatment.
Mesenchymal stem/stromal cells: dedicator to maintain tumor homeostasis.
Cell-cell interactions mediating primary and metastatic breast cancer dormancy.
Extrinsic and Cell-Intrinsic Stress in the Immune Tumor Micro-Environment.
Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.
Remodeling of tumor microenvironment by cellular senescence and immunosenescence in cervical cancer.
Patient-derived tumor organoid and fibroblast assembloid models for interrogation of the tumor microenvironment in esophageal adenocarcinoma.
The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment.
Assessing Novel Antibody-Based Therapies in Reconstructive 3D Cell Models of the Tumor Microenvironment.

Int J Mol Sci. 2024 Nov 14. pii: 12223. [Epub ahead of print]25(22):

Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.

Jing Wang, Yuanli He, Feiming Hu, Chenchen Hu, Yuanjie Sun, Kun Yang, Shuya Yang.

  Metabolic reprogramming of immune cells within the tumor microenvironment (TME) plays a pivotal role in shaping tumor progression and responses to therapy. The intricate interplay between tumor cells and immune cells within this ecosystem influences their metabolic landscapes, thereby modulating the immune evasion tactics employed by tumors and the efficacy of immunotherapeutic interventions. This review delves into the metabolic reprogramming that occurs in tumor cells and a spectrum of immune cells, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs), within the TME. The metabolic shifts in these cell types span alterations in glucose, lipid, and amino acid metabolism. Such metabolic reconfigurations can profoundly influence immune cell function and the mechanisms by which tumors evade immune surveillance. Gaining a comprehensive understanding of the metabolic reprogramming of immune cells in the TME is essential for devising novel cancer therapeutic strategies. By targeting the metabolic states of immune cells, it is possible to augment their anti-tumor activities, presenting new opportunities for immunotherapeutic approaches. These strategies hold promise for enhancing treatment outcomes and circumventing the emergence of drug resistance.

Keywords:  immune cells; immunotherapy; metabolic reprogramming; the tumor microenvironment

DOI:  https://doi.org/10.3390/ijms252212223
Breast Cancer. 2024 Nov 26.

The complex role of regulatory cells in breast cancer: implication for immunopathogenesis and immunotherapy.

RuiJuan Guo, Ping Wang.

  Breast cancers (BCs) are frequently linked to an immunosuppressive microenvironment that facilitates tumor evasion of anti-cancer immunity. The cells that suppress the immune system such as regulatory B cells (Bregs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), play a crucial role in immune resistance. Also, tumor progression and immune evasion of cancers are facilitated by cytokines and factors released by tumor cells or immunosuppressive cells. Targeting these regulatory cells therapeutically, whether through elimination, inactivation, or reprogramming, has resulted in hopeful anti-tumor reactions. Yet, the substantial diversity and adaptability of these cells, both in terms of appearance and function, as well as their variation over time and depending on where they are in the body, have posed significant challenges for using them as reliable biomarkers and creating focused therapies that could target their creation, growth, and various tumor-promoting roles. The immunotherapy approaches in BC and their effectiveness in treating certain subtypes are still in their initial phases. In this review, we thoroughly outlined the characteristics, roles, and possible treatment options for these immune-suppressing cells in the tumor environment.

Keywords:  Breast cancer; Immune cells; Immunotherapy; MDSC; Regulatory T cell

DOI:  https://doi.org/10.1007/s12282-024-01654-7
Front Pharmacol. 2024 ;15 1481850

Natural products: promising therapeutics for targeting regulatory immune cells in the tumor microenvironment.

Peng Song, Fei Song, Tingting Shao, Pengjuan Wang, Rongkun Li, Zhe-Sheng Chen, Zhaofang Zhang, Guozhong Xue.

  Regulatory immune cells regulate immune responses through various mechanisms, affecting the occurrence, development, and therapeutic effects of tumors. In this article, we reviewed the important roles of regulatory immune cells, such as regulatory T cells (Tregs), regulatory B cells (Bregs), myeloid-derived suppressor cells (MDSCs), regulatory dendritic cells (DCregs), and tumor-associated macrophages (TAMs), in the tumor microenvironment (TME). The immunomodulatory effects of natural products, such as polysaccharides, polyphenols, glycosides, alkaloids, terpenoids, quinones, and other compounds, which affect the functions of regulatory immune cells through molecular signaling pathways, thereby enhancing the potential of the antitumor immune response, are discussed. These findings provide new ideas and possibilities for the application of natural products in tumor treatment, which can help enhance the effectiveness of tumor treatment and improve patient prognosis.

Keywords:  natural products; polyphenols; polysaccharides; regulatory immune cells; tumor therapy

DOI:  https://doi.org/10.3389/fphar.2024.1481850
J Exp Clin Cancer Res. 2024 Nov 30. 43(1): 315

Ferroptosis and the tumor microenvironment.

Kaisa Cui, Kang Wang, Zhaohui Huang.

  Ferroptosis is a type of regulated cell death characterized by its non-apoptotic, iron-dependent and oxidative nature. Since its discovery in 2012, extensive research has demonstrated its pivotal roles in tumorigenesis, metastasis and cancer therapy. The tumor microenvironment (TME) is a complex ecosystem comprising cancer cells, non-cancer cells, extracellular matrix, metabolites and cytokines. Recent studies have underscored a new paradigm in which non-cancer cells in the TME, such as immune and stromal cells, also play significant roles in regulating tumor progression and therapeutic resistance typically through complicated crosstalk with cancer cells. Notably, this crosstalk in the TME were partially mediated through ferrotopsis-related mechanisms. This review provides a comprehensive and systematic summary of the current findings concerning the roles of ferroptosis in the TME and how ferroptosis-mediated TME reprogramming impacts cancer therapeutic resistance and progression. Additionally, this review outlines various ferroptosis-related therapeutic strategies aimed at targeting the TME.

Keywords:  CD8+ T cell; Cancer-associated fibroblast; Ferroptosis; Immunotherapy; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.1186/s13046-024-03235-0
Cancers (Basel). 2024 Nov 13. pii: 3810. [Epub ahead of print]16(22):

Harnessing Bacterial Agents to Modulate the Tumor Microenvironment and Enhance Cancer Immunotherapy.

Christina James Thomas, Kaylee Delgado, Kamlesh Sawant, Jacob Roy, Udit Gupta, Carly Shaw Song, Rayansh Poojary, Paul de Figueiredo, Jianxun Song.

  Cancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to attack tumors. However, its effectiveness is often hindered by the immunosuppressive tumor microenvironment (TME), where a complex interplay of tumor, stromal, and immune cells undermines antitumor responses and allows tumors to evade immune detection. This review explores innovative strategies to modify the TME and enhance immunotherapy outcomes, focusing on the therapeutic potential of engineered bacteria. These bacteria exploit the unique characteristics of the TME, such as abnormal vasculature and immune suppression, to selectively accumulate in tumors. Genetically modified bacteria can deliver therapeutic agents, including immune checkpoint inhibitors and cytokines, directly to tumor sites. This review highlights how bacterial therapeutics can target critical immune cells within the TME, such as myeloid-derived suppressor cells and tumor-associated macrophages, thereby promoting antitumor immunity. The combination of bacterial therapies with immune checkpoint inhibitors or adoptive cell transfer presents a promising strategy to counteract immune suppression. Continued research in this area could position bacterial agents as a powerful new modality to reshape the TME and enhance the efficacy of cancer immunotherapy, particularly for tumors resistant to conventional treatments.

Keywords:  antitumor immunity; bacterial therapeutics; cancer immunotherapy; engineered bacteria; immune checkpoint inhibitors; immunosuppression; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers16223810
Cells. 2024 Nov 20. pii: 1924. [Epub ahead of print]13(22):

Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy.

Md Ataur Rahman, Mahesh Kumar Yadab, Meser M Ali.

  Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function and contributes to immunotherapy failure. However, acidic conditions in the TME disrupt the interaction between cancer and immune cells, driving tumor-infiltrating T cells and NK cells into an inactivated, anergic state. Simultaneously, acidosis promotes the recruitment and activation of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells (Tregs). Notably, tumor acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor acidity thus acts as a "protective shield," neutralizing anti-tumor immune responses and transforming immune cells into pro-tumor allies. Therefore, targeting lactate metabolism has emerged as a promising strategy to overcome this barrier, with approaches including buffer agents to neutralize acidic pH and inhibitors to block lactate production or transport, thereby restoring immune cell efficacy in the TME. Recent discoveries have identified genes involved in extracellular pH (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims to elucidate the molecular mechanisms driving extracellular acidification and to develop treatments that modulate pH levels to enhance immunotherapy outcomes. Additionally, future clinical studies are crucial to validate the safety and efficacy of pHe-targeted therapies in cancer patients. Thus, this review explores the regulation of pHe in the TME and its potential role in improving cancer immunotherapy.

Keywords:  T cells; acidic TME; extracellular pH; immunotherapy resistance; lactate metabolism; tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cells13221924
Biochim Biophys Acta Rev Cancer. 2024 Nov 25. pii: S0304-419X(24)00156-2. [Epub ahead of print] 189225

Targeting extracellular matrix interaction in gastrointestinal cancer: Immune modulation, metabolic reprogramming, and therapeutic strategies.

Jiyifan Li, Wenxin Zhang, Lu Chen, Xinhai Wang, Jiafeng Liu, Yuxin Huang, Huijie Qi, Li Chen, Tianxiao Wang, Qunyi Li.

  The extracellular matrix (ECM) is a major constituent of the tumor microenvironment, acting as a mediator that supports the progression of gastrointestinal (GI) cancers, particularly in mesenchymal subtypes. Beyond providing structural support, the ECM actively shapes the tumor microenvironment (TME) through complex biochemical and biomechanical remodeling. Dysregulation of ECM composition and signaling is closely linked to increased cancer aggressiveness, poor prognosis, and resistance to therapy. ECM components, such as collagen, fibronectin, laminin, and periostin, influence tumor growth, metastasis, immune modulation, and metabolic reprogramming by interacting with tumor cells, immune cells, and cancer-associated fibroblasts. In this review, we highlight the heterogeneous nature of the ECM and the dualistic roles of its components across GI cancers, with a focus on their contributions to immune evasion and metabolic remodeling via intercellular interactions. Additionally, we explore therapeutic strategies targeting ECM remodeling and ECM-centered interactions, emphasizing their potential in enhancing existing anti-tumor therapies.

Keywords:  Extracellular matrix; Gastrointestinal cancer; Immunotherapy; Tumor metabolism; Tumor microenvironment; cancer-associated fibroblast

DOI:  https://doi.org/10.1016/j.bbcan.2024.189225
Mol Cancer. 2024 Nov 30. 23(1): 268

Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication.

Hua Wang, Tao Wang, Shuxiang Yan, Jinxin Tang, Yibo Zhang, Liming Wang, Haodong Xu, Chao Tu.

  In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.

Keywords:  Clinical implication; Cytokine; Mechanism; Pyroptosis; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-024-02183-9
Front Pharmacol. 2024 ;15 1442888

Tumor microenvironment and cancer metastasis: molecular mechanisms and therapeutic implications.

Cigir Biray Avci, Bakiye Goker Bagca, Masoud Nikanfar, Leila Sabour Takanlou, Maryam Sabour Takanlou, Alireza Nourazarian.

  The tumor microenvironment (TME) plays a crucial role in cancer development and metastasis. This review summarizes the current research on how the TME promotes metastasis through molecular pathways, focusing on key components, such as cancer-associated fibroblasts, immune cells, endothelial cells, cytokines, and the extracellular matrix. Significant findings have highlighted that alterations in cellular communication within the TME enable tumor cells to evade immune surveillance, survive, and invade other tissues. This review highlights the roles of TGF-β and VEGF signaling in promoting angiogenesis and extracellular matrix remodeling, which facilitate metastasis. Additionally, we explored how metabolic reprogramming of tumor and stromal cells, influenced by nutrient availability in the TME, drives cancer progression. This study also evaluated the therapeutic strategies targeting these interactions to disrupt metastasis. By providing a multidisciplinary perspective, this study suggests that understanding the molecular basis of the TME can lead to more effective cancer therapies and identify potential avenues for future research. Future research on the TME should prioritize unraveling the molecular and cellular interactions within this complex environment, which could lead to novel therapeutic strategies and personalized cancer treatments. Moreover, advancements in technologies such as single-cell analysis, spatial transcriptomics, and epigenetic profiling offer promising avenues for identifying new therapeutic targets and improving the efficacy of immunotherapies, particularly in the context of metastasis.

Keywords:  cancer metastasis; cellular microenvironment; molecular mechanisms; signal transduction; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2024.1442888
Biology (Basel). 2024 Nov 04. pii: 898. [Epub ahead of print]13(11):

Progression of the Immune Escape Mechanism in Tumors.

Sheila Spada, Sumit Mukherjee.

There exists a long-standing research interest to understand the molecular and signaling interactions between tumor cells and the innate and adaptive immune cells such as dendritic cells, macrophages, NK cells, and B and T cells that occur in the tumor microenvironment (TME) [...].

DOI: https://doi.org/10.3390/biology13110898
J Exp Clin Cancer Res. 2024 Nov 28. 43(1): 312

Understanding the role of TNFR2 signaling in the tumor microenvironment of breast cancer.

Ali Mussa, Nor Hayati Ismail, Mahasin Hamid, Mohammad A I Al-Hatamleh, Anthony Bragoli, Khalid Hajissa, Noor Fatmawati Mokhtar, Rohimah Mohamud, Vuk Uskoković, Rosline Hassan.

  Breast cancer (BC) is the most frequently diagnosed malignancy among women. It is characterized by a high level of heterogeneity that emerges from the interaction of several cellular and soluble components in the tumor microenvironment (TME), such as cytokines, tumor cells and tumor-associated immune cells. Tumor necrosis factor (TNF) receptor 2 (TNFR2) appears to play a significant role in microenvironmental regulation, tumor progression, immune evasion, drug resistance, and metastasis of many types of cancer, including BC. However, the significance of TNFR2 in BC biology is not fully understood. This review provides an overview of TNFR2 biology, detailing its activation and its interactions with important signaling pathways in the TME (e.g., NF-κB, MAPK, and PI3K/Akt pathways). We discuss potential therapeutic strategies targeting TNFR2, with the aim of enhancing the antitumor immune response to BC. This review provides insights into role of TNFR2 as a major immune checkpoint for the future treatment of patients with BC.

Keywords:  CD120b; Immune checkpoint; Immunosuppressive TME; TNF; TNFRSF1B

DOI:  https://doi.org/10.1186/s13046-024-03218-1
Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01350-0. [Epub ahead of print]43(11): 114999

Q&A with Ilaria Elia.

Ilaria Elia.

  Ilaria Elia, guest editor of the cancer metabolism special issue, spoke with Cell Reports about her scientific interests and her lab's focus on investigating the metabolic interactions between cancer cells and immune cells within the tumor microenvironment. Ilaria also discussed recent developments and future directions in the field.

Keywords:  CP: Cancer; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114999
Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01351-2. [Epub ahead of print]43(11): 115000

Q&A with Ping Gao.

Ping Gao.

  Ping Gao, guest editor of the cancer metabolism special issue, spoke with Cell Reports about his scientific interests and his lab's focus on investigating the metabolic reprogramming in cancer cells and immune cells in the tumor microenvironment. Ping also discussed recent developments and future directions in the field.

Keywords:  CP: Cancer; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.115000
MedComm (2020). 2024 Dec;5(12): e70019

Exosomal circular RNAs in tumor microenvironment: An emphasis on signaling pathways and clinical opportunities.

Junshu Li, Wencheng Zhou, Huiling Wang, Meijuan Huang, Hongxin Deng.

  Exosomes can regulate the malignant progression of tumors by carrying a variety of genetic information and transmitting it to target cells. Recent studies indicate that exosomal circular RNAs (circRNAs) regulate multiple biological processes in carcinogenesis, such as tumor growth, metastasis, epithelial-mesenchymal transition, drug resistance, autophagy, metabolism, angiogenesis, and immune escape. In the tumor microenvironment (TME), exosomal circRNAs can be transferred among tumor cells, endothelial cells, cancer-associated fibroblasts, immune cells, and microbiota, affecting tumor initiation and progression. Due to the high stability and widespread presence of exosomal circRNAs, they hold promise as biomarkers for tumor diagnosis and prognosis prediction in blood and urine. In addition, designing nanoparticles targeting exosomal circRNAs and utilizing exosomal circRNAs derived from immune cells or stem cells provide new strategies for cancer therapy. In this review, we examined the crucial role of exosomal circRNAs in regulating tumor-related signaling pathways and summarized the transmission of exosomal circRNAs between various types of cells and their impact on the TME. Finally, our review highlights the potential of exosomal circRNAs as diagnostic and prognostic prediction biomarkers, as well as suggesting new strategies for clinical therapy.

Keywords:  biomarker; circRNA; exosome; tumor microenvironment; tumor therapy

DOI:  https://doi.org/10.1002/mco2.70019
Int Rev Immunol. 2024 Nov 29. 1-24

Boosting antitumor immunity in breast cancers: Potential of adjuvants, drugs, and nanocarriers.

Ping Chen, Lei Ren, Youwei Guo, Yan Sun.

  Despite advancements in breast cancer treatment, therapeutic resistance, and tumor recurrence continue to pose formidable challenges. Therefore, a deep knowledge of the intricate interplay between the tumor and the immune system is necessary. In the pursuit of combating breast cancer, the awakening of antitumor immunity has been proposed as a compelling avenue. Tumor stroma in breast cancers contains multiple stromal and immune cells that impact the resistance to therapy and also the expansion of malignant cells. Activating or repressing these stromal and immune cells, as well as their secretions can be proposed for exhausting resistance mechanisms and repressing tumor growth. NK cells and T lymphocytes are the prominent components of breast tumor immunity that can be triggered by adjuvants for eradicating malignant cells. However, stromal cells like endothelial and fibroblast cells, as well as some immune suppressive cells, consisting of premature myeloid cells, and some subsets of macrophages and CD4+ T lymphocytes, can dampen antitumor immunity in favor of breast tumor growth and therapy resistance. This review article aims to research the prospect of harnessing the power of drugs, adjuvants, and nanoparticles in awakening the immune reactions against breast malignant cells. By investigating the immunomodulatory properties of pharmacological agents and the synergistic effects of adjuvants, this review seeks to uncover the mechanisms through which antitumor immunity can be triggered. Moreover, the current review delineates the challenges and opportunities in the translational journey from bench to bedside.

Keywords:  Adjuvants; antitumor immunity; breast cancer; nanoparticles; tumor stroma

DOI:  https://doi.org/10.1080/08830185.2024.2432499
Cells. 2024 Nov 19. pii: 1909. [Epub ahead of print]13(22):

The Clinical Significance of Cancer-Associated Fibroblasts Classification in Non-Small Cell Lung Cancer.

Kostas A Papavassiliou, Amalia A Sofianidi, Vassiliki A Gogou, Athanasios G Papavassiliou.

Malignant cells flourish within a specialized environment known as the tumor microenvironment (TME) [...].

DOI: https://doi.org/10.3390/cells13221909
J Transl Med. 2024 Nov 28. 22(1): 1076

CAR-armored-cell therapy in solid tumor treatment.

Yan Liu, Lin Xiao, Mingxuan Yang, Xuemei Chen, Hongyue Liu, Quanxing Wang, Meng Guo, Jianhua Luo.

  Over the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a revolutionary immunotherapeutic approach to combat cancer. This therapy constructs a CAR on the surface of T cells through genetic engineering techniques. The CAR is formed from a combination of antibody-derived or ligand-derived domains and T-cell receptor (TCR) domains. This enables T cells to specifically bind to and activate against tumor cells. However, the efficacy of CAR-T cells in solid tumors remains inconclusive due to several challenges such as poor tumor trafficking, infiltration, and the immunosuppressive tumor microenvironment (TME). In response, CAR natural killer (CAR-NK) and CAR macrophages (CAR-M) have been developed as complementary strategies for solid tumors. CAR-NK cells do not require HLA compatibility, demonstrate reduced toxicity, and are thus seen as potential substitutes for CAR-T cells. Furthermore, CAR-M immunotherapy is also being researched and has shown phagocytic capabilities and tumor-antigen presentation. This study discusses the features, advantages, and limitations of CAR-T, CAR-NK, and CAR-M cells in the treatment of solid tumors and suggests prospective solutions for enhancing the efficacy of CAR host-cell-based immunotherapy.

Keywords:  CAR-M; CAR-NK; CAR-T; Solid tumor

DOI:  https://doi.org/10.1186/s12967-024-05903-3
Hum Cell. 2024 Nov 28. 38(1): 21

Mesenchymal stem/stromal cells: dedicator to maintain tumor homeostasis.

Juncun Yao, Li Sun, Feng Gao, Wei Zhu.

  Mesenchymal stem/stromal cells （MSCs） act as a factor in tumor recurrence after drug treatment with their involvement observed in various cancer types. As a constituent of the tumor microenvironment (TME), MSCs not only provide support to tumor growth but also establish connections with diverse cell populations within the TME, serving as mediators linking different tumor-associated components. MSCs play an important role in maintaining tumor progression due to their stem cell properties and remarkable differentiation capacity. Given the intensification of tumor research and the encouraging results achieved in recent years，the aim of this article is to investigate the supportive role of MSCs in tumor cells as well as in various cellular and non-cellular components of the tumor microenvironment. Furthermore, the article shows that MSCs do not have a specific anatomical ecological niche and describes the contribution of MSCs to the maintenance of tumor homeostasis on the basis of homing, plasticity and tumor-forming properties. By elucidating the critical roles of different components of TME, this study provides a comprehensive understanding of tumor therapy and may offer new insights into defeating cancer.

Keywords:  Epithelial–mesenchymal transition; Immunosuppression; Metastasis; Proliferation; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13577-024-01154-y
Cancer Metastasis Rev. 2024 Nov 25. 44(1): 6

Cell-cell interactions mediating primary and metastatic breast cancer dormancy.

Nicholas A Lenart, Shreyas S Rao.

  Breast cancer remains one of the leading causes of death in women around the world. A majority of deaths from breast cancer occur due to cancer cells colonizing distant organ sites. When colonizing these distant organ sites, breast cancer cells have been known to enter into a state of dormancy for extended periods of time. However, the mechanisms that promote dormancy as well as dormant-to-proliferative switch are not fully understood. The tumor microenvironment plays a key role in mediating cancer cell phenotype including regulation of the dormant state. In this review, we highlight cell-cell interactions in the tumor microenvironment mediating breast cancer dormancy at the primary and metastatic sites. Specifically, we describe how immune cells from the lymphoid lineage, tumor-associated myeloid lineage cells, and stromal cells of non-hematopoietic origin as well as tissue resident stromal cells impact dormancy vs. proliferation in breast cancer cells as well as the associated mechanisms. In addition, we highlight the importance of developing model systems and the associated considerations that will be critical in unraveling the mechanisms that promote primary and metastatic breast cancer dormancy mediated via cell-cell interactions.

Keywords:  Breast cancer; Cell-cell interactions; Dormancy; Metastasis

DOI:  https://doi.org/10.1007/s10555-024-10223-5
Int J Mol Sci. 2024 Nov 19. pii: 12403. [Epub ahead of print]25(22):

Extrinsic and Cell-Intrinsic Stress in the Immune Tumor Micro-Environment.

Aldo Ummarino, Nicholas Calà, Paola Allavena.

  In continuously progressive tumor tissues, the causes of cellular stress are multiple: metabolic alterations, nutrient deprivation, chronic inflammation and hypoxia. To survive, tumor cells activate the stress response program, a highly conserved molecular reprogramming proposed to cope with challenges in a hostile environment. Not only cancer cells are affected, but stress responses in tumors also have a profound impact on their normal cellular counterparts: fibroblasts, endothelial cells and infiltrating immune cells. In recent years, there has been a growing interest in the interaction between cancer and immune cells, especially in difficult conditions of cellular stress. A growing literature indicates that knowledge of the molecular pathways activated in tumor and immune cells under stress conditions may offer new insights for possible therapeutic interventions. Counter-regulating the stress caused by the presence of a growing tumor can therefore be a weapon to limit disease progression. Here, we review the main pathways activated in cellular stress responses with a focus on immune cells present in the tumor microenvironment.

Keywords:  cancer-related inflammation; hypoxia; metabolism; tumor micro-environment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/ijms252212403
Int Immunopharmacol. 2024 Nov 26. pii: S1567-5769(24)02224-0. [Epub ahead of print]144 113702

Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.

Shouhua Li, Hengtong Han, Kaili Yang, Xiaoxiao Li, Libin Ma, Ze Yang, Yong-Xun Zhao.

  The metabolic reprogramming of cancer cells is a hallmark of many malignancies. To meet the energy acquisition needs of tumor cells for rapid proliferation, tumor cells reprogram their nutrient metabolism, which is caused by the abnormal expression of transcription factors and signaling molecules related to energy metabolic pathways as well as the upregulation and downregulation of abnormal metabolic enzymes, receptors, and mediators. Thyroid cancer (TC) is the most common endocrine tumor, and immunotherapy has become the mainstream choice for clinical benefit after the failure of surgical, endocrine, and radioiodine therapies. TC change the tumor microenvironment (TME) through nutrient competition and metabolites, causing metabolic reprogramming of immune cells, profoundly changing immune cell function, and promoting immune evasion of tumor cells. A deeper understanding of how metabolic reprogramming alters the TME and controls immune cell fate and function will help improve the effectiveness of TC immunotherapy and patient outcomes. This paper aims to elucidate the metabolic communication that occurs between immune cells around TC and discusses how metabolic reprogramming in TC affects the immune microenvironment and the effectiveness of anti-cancer immunotherapy. Finally, targeting key metabolic checkpoints during metabolic reprogramming, combined with immunotherapy, is a promising strategy.

Keywords:  Immune microenvironment; Immunometabolism; Immunotherapy; Metabolic reprogramming; Thyroid cancers

DOI:  https://doi.org/10.1016/j.intimp.2024.113702
Semin Cancer Biol. 2024 Nov 23. pii: S1044-579X(24)00086-5. [Epub ahead of print]108 17-32

Remodeling of tumor microenvironment by cellular senescence and immunosenescence in cervical cancer.

Yijiang He, Yue Qiu, Xiansong Yang, Guimei Lu, Shan-Shan Zhao.

  Cellular senescence is a response to various stress signals, which is characterized by stable cell cycle arrest, alterations in cellular morphology, metabolic reprogramming and production of senescence-associated secretory phenotype (SASP). When it occurs in the immune system, it is called immunosenescence. Cervical cancer is a common gynecological malignancy, and cervical cancer screening is generally recommended before the age of 65. Elderly women (≥65 years) are more often diagnosed with advanced disease and have poorer prognosis compared to younger patients. Despite extensive research, the tumor microenvironment requires more in-depth exploration, particularly in elderly patients. In cervical cancer, senescent cells have a double-edged sword effect on tumor progression. Induction of preneoplastic cell senescence prevents tumor initiation, and several treatment approaches of cervical cancer act in part by inducing cancer cell senescence. However, senescent immune cell populations within the tumor microenvironment facilitate tumor development, recurrence, treatment resistance, etc. Amplification of beneficial effects and inhibition of aging-related pro-tumorigenic pathways contribute to improving antitumor effects. This review discusses senescent cancer and immune cells present in the tumor microenvironment of cervical cancer and how these senescent cells and their SASP remodel the tumor microenvironment, influence antitumor immunity and tumor initiation and development. Moreover, we discuss the significance of senotherapeutics that enable to eliminate senescent cells and prevent tumor progression and development through improving antitumor immunity and affecting the tumor microenvironment.

Keywords:  Cellular senescence; Cervical cancer; Immunosenescence; Senotherapeutics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2024.11.002
Cell Rep Methods. 2024 Nov 20. pii: S2667-2375(24)00299-6. [Epub ahead of print] 100909

Patient-derived tumor organoid and fibroblast assembloid models for interrogation of the tumor microenvironment in esophageal adenocarcinoma.

Benjamin P Sharpe, Liliya A Nazlamova, Carmen Tse, David A Johnston, Jaya Thomas, Rhianna Blyth, Oliver J Pickering, Ben Grace, Jack Harrington, Rushda Rajak, Matthew Rose-Zerilli, Zoe S Walters, Tim J Underwood.

  The tumor microenvironment (TME) comprises all non-tumor elements of cancer and strongly influences disease progression and phenotype. To understand tumor biology and accurately test new therapeutic strategies, representative models should contain both tumor cells and normal cells of the TME. Here, we describe and characterize co-culture tumor-derived organoids and cancer-associated fibroblasts (CAFs), a major component of the TME, in matrix-embedded assembloid models of esophageal adenocarcinoma (EAC). We demonstrate that the assembloid models faithfully recapitulate the differentiation status of EAC and different CAF phenotypes found in the EAC patient TME. We evaluate cell phenotypes by combining tissue-clearing techniques with whole-mount immunofluorescence and histology, providing a practical framework for the characterization of cancer assembloids.

Keywords:  CP: Cancer biology; CP: Stem cell; assembloids; cancer-associated fibroblasts; esophageal adenocarcinoma; organoids; tumor microenvironment

DOI:  https://doi.org/10.1016/j.crmeth.2024.100909
Cancer Immunol Res. 2024 Nov 27.

The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment.

Ayaka Tsuge, Sho Watanabe, Akihito Kawazoe, Yosuke Togashi, Kota Itahashi, Mari Masuda, Atsuo Sai, Shogo Takei, Hiromi Muraoka, Shuichi Ohkubo, Daisuke Sugiyama, Yue Yan, Shota Fukuoka, Toshihiko Doi, Kohei Shitara, Shohei Koyama, Hiroyoshi Nishikawa.

Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to programmed death (PD)-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment (TME), has been intensively studied. Inhibition of heat shock protein 90 (HSP90), a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects. Here, we show that the number of Treg cells are selectively reduced by the HSP90 inhibitor pimitespib in animal models and patients with gastric cancer in a clinical trial (EPOC1704). Pimitespib reduced the highly immunosuppressive human FOXP3high effector Treg cells by inhibiting their proliferation and decreasing their expression of effector molecules, which improved the priming and activation of antigen-specific CD8+ T cells. Mechanistic studies revealed that pimitespib selectively degraded STAT5, a key transducer of the IL-2 signaling pathway, which is essential for Treg cell development and maintenance, and consequently compromised FOXP3 expression, leading to selective impairment of immunosuppression in the TME by Treg cells. Thus, pimitespib treatment combined with PD-1 blockade exhibited a far stronger antitumor effect than either treatment alone in animal models. Through these data, we propose that HSP90 inhibition is a promising therapeutic option for Treg cell-targeted cancer immunotherapy.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0713
Adv Biol (Weinh). 2024 Nov 27. e2400431

Assessing Novel Antibody-Based Therapies in Reconstructive 3D Cell Models of the Tumor Microenvironment.

Giacomo Domenici, Nuno F Lopes, Gonçalo Trindade, Isabella Ramella Gal, Joan Miret Minard, Sofia P Rebelo, Catarina Freitas, Nádia Duarte, Catarina Brito.

  Targeted, combinatorial, and immunomodulatory therapies, such as antibody-drug conjugates (ADCs) and immunomodulatory antibodies (Abs), are powerful weapons against tumor cells and immune cells within the tumor microenvironment (TME). Therefore, the evaluation of such therapies should be conducted in pre-clinical models able to recapitulate the complex cellular and molecular crosstalk of the TME. To build-in critical hallmarks of the TME, a breast cancer heterotypic 3D cell model (3D-3) is devised using a microencapsulation strategy with an inert biomaterial (alginate) and agitation-based cultures. Both stromal and immune components are added to multicellular tumor spheroids, therefore fostering cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) immunomodulatory interactions. The potential of the methodology to assess Ab-based therapies is then addressed by employing a series of anti-HER2-based ADCs. ADCs induced tumor-cell specific cytotoxicity toward HER2+ breast cancer spheroids while sparing HER2-negative CAFs. In addition, an immunomodulatory blocking Ab against colony-stimulating factor 1 receptor (CSF1R) decreases the expression of immunosuppressive and anti-inflammatory markers in TAMs, like what is previously observed upon in vivo α-CSF1R administration. Collectively, the human TME-based 3D-3 cell model is a suitable tool to evaluate the anti-tumor and immunomodulatory potential of novel antibody-based therapies directed against TME targets, such as cancer cells and macrophages.

Keywords:  3D cancer models; antibody‐drug conjugates; cancer‐associated fibroblasts; targeted therapies; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/adbi.202400431