bims-flamet 2024-07-07 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024‒07‒07
thirty papers selected by
Peio Azcoaga, Biodonostia HRI

The significance of lipid metabolism reprogramming of tumor-associated macrophages in hepatocellular carcinoma.
Tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for hepatocellular carcinoma: recent research progress.
Revisiting the role of mesenchymal stromal cells in cancer initiation, metastasis and immunosuppression.
Endothelial cell Notch signaling programs cancer-associated fibroblasts to promote tumor immune evasion.
Engineered CD147-CAR macrophages for enhanced phagocytosis of cancers.
Metabolic crosstalk: Extracellular ATP and the tumor microenvironment in cancer progression and therapy.
Glycosylation in the tumor immune response: the bitter side of sweetness.
O-GlcNAc signaling: implications for stress-induced adaptive response pathway in the tumor microenvironment.
Generation and Functional Verification of Hypoxia-sensitive Chimeric Antigen Receptor-T Cells.
[Research progress in macrophage migration inhibitory factor (MIF) in tumor immune response].
Inhibition of glutamine metabolism: acting on tumoral cells or on tumor microenvironment?
[Characteristics of the tumor microenvironment and therapeutic progress in malignant pleural effusion].
Mechanistic insights into mesenchymal-amoeboid transition as an intelligent cellular adaptation in cancer metastasis and resistance.
Cell of origin alters myeloid-mediated immunosuppression in lung adenocarcinoma.
Do Not Forget the Granulocytic Compartment's Role in T cell-Mediated Antitumor Immunity.
Modulating cancer mechanopathology to restore vascular function and enhance immunotherapy.
Impact of high-salt diet in health and diseases and its role in pursuit of cancer immunotherapy by modulating gut microbiome.
Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression.
The role of histamine and its receptors in breast cancer: from pathology to therapeutic targets.
Impact of fludarabine and treosulfan on ovarian tumor cells and mesothelin chimeric antigen receptor T cells.
Glucocorticoid Receptors Orchestrate a Convergence of Host and Cellular Stress Signals in Triple Negative Breast Cancer.
M2-type tumor-associated macrophages upregulated PD-L1 expression in cervical cancer via the PI3K/AKT pathway.
Binding of interleukin-1 receptor antagonist to cholinergic receptor muscarinic 4 promotes immunosuppression and neuroendocrine differentiation in prostate cancer.
Towards targeting the breast cancer immune microenvironment.
Mechanisms of triple-negative breast cancer extravasation: Impact of the physical environment and endothelial glycocalyx.
DDR2/STAT3 positive feedback loop mediates the immunosuppressive microenvironment by upregulating PD-L1 and recruiting MDSCs in oxaliplatin-resistant HCC.
Genetically engineering glycolysis in T cells increases their antitumor function.
Modulatory effects of cancer stem cell-derived extracellular vesicles on the tumor immune microenvironment.
Tumoral EIF4EBP1 regulates the crosstalk between tumor-associated macrophages and tumor cells in MRTK.
Heterogeneity of cancer-associated fibroblasts and tumor-promoting roles in head and neck squamous cell carcinoma.

Cancer Immunol Immunother. 2024 Jul 02. 73(9): 171

The significance of lipid metabolism reprogramming of tumor-associated macrophages in hepatocellular carcinoma.

Qingjian Xie, Yuan Zeng, Xiangting Zhang, Fujun Yu.

  In the intricate landscape of the tumor microenvironment, tumor-associated macrophages (TAMs) emerge as a ubiquitous cellular component that profoundly affects the oncogenic process. The microenvironment of hepatocellular carcinoma (HCC) is characterized by a pronounced infiltration of TAMs, underscoring their pivotal role in modulating the trajectory of the disease. Amidst the evolving therapeutic paradigms for HCC, the strategic reprogramming of metabolic pathways presents a promising avenue for intervention, garnering escalating interest within the scientific community. Previous investigations have predominantly focused on elucidating the mechanisms of metabolic reprogramming in cancer cells without paying sufficient attention to understanding how TAM metabolic reprogramming, particularly lipid metabolism, affects the progression of HCC. In this review article, we intend to elucidate how TAMs exert their regulatory effects via diverse pathways such as E2F1-E2F2-CPT2, LKB1-AMPK, and mTORC1-SREBP, and discuss correlations of TAMs with these processes and the characteristics of relevant pathways in HCC progression by consolidating various studies on TAM lipid uptake, storage, synthesis, and catabolism. It is our hope that our summary could delineate the impact of specific mechanisms underlying TAM lipid metabolic reprogramming on HCC progression and provide useful information for future research on HCC and the development of new treatment strategies.

Keywords:  Hepatocellular carcinoma; Lipid metabolic reprogramming; Tumor microenvironments; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/s00262-024-03748-9
Front Pharmacol. 2024 ;15 1382256

Tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for hepatocellular carcinoma: recent research progress.

Ziwei Li, Dongyu Duan, Li Li, Dan Peng, Yue Ming, Rui Ni, Yao Liu.

  Hepatocellular carcinoma (HCC) is one of the cancers that seriously threaten human health. Immunotherapy serves as the mainstay of treatment for HCC patients by targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. However, the effectiveness of anti-PD-1/PD-L1 treatment is limited when HCC becomes drug-resistant. Tumor-associated macrophages (TAMs) are an important factor in the negative regulation of PD-1 antibody targeted therapy in the tumor microenvironment (TME). Therefore, as an emerging direction in cancer immunotherapy research for the treatment of HCC, it is crucial to elucidate the correlations and mechanisms between TAMs and PD-1/PD-L1-mediated immune tolerance. This paper summarizes the effects of TAMs on the pathogenesis and progression of HCC and their impact on HCC anti-PD-1/PD-L1 immunotherapy, and further explores current potential therapeutic strategies that target TAMs in HCC, including eliminating TAMs in the TME, inhibiting TAMs recruitment to tumors and functionally repolarizing M2-TAMs (tumor-supportive) to M1-TAMs (antitumor type).

Keywords:  PD-1/PD-L1; T cell; hepatocellular carcinoma (HCC); immunotherapy; tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3389/fphar.2024.1382256
Exp Hematol Oncol. 2024 Jul 01. 13(1): 64

Revisiting the role of mesenchymal stromal cells in cancer initiation, metastasis and immunosuppression.

Yanyan Zhang, Charles Wang, Jian Jian Li.

  Immune checkpoint blockade (ICB) necessitates a thorough understanding of intricate cellular interactions within the tumor microenvironment (TME). Mesenchymal stromal cells (MSCs) play a pivotal role in cancer generation, progression, and immunosuppressive tumor microenvironment. Within the TME, MSCs encompass both resident and circulating counterparts that dynamically communicate and actively participate in TME immunosurveillance and response to ICB. This review aims to reevaluate various facets of MSCs, including their potential self-transformation to function as cancer-initiating cells and contributions to the creation of a conducive environment for tumor proliferation and metastasis. Additionally, we explore the immune regulatory functions of tumor-associated MSCs (TA-MSCs) and MSC-derived extracellular vesicles (MSC-EVs) with analysis of potential connections between circulating and tissue-resident MSCs. A comprehensive understanding of the dynamics of MSC-immune cell communication and the heterogeneous cargo of tumor-educated versus naïve MSCs may unveil a new MSC-mediated immunosuppressive pathway that can be targeted to enhance cancer control by ICB.

Keywords:  Immunosuppression; Immunotherapy; Mesenchymal stromal cells; Radiotherapy; Tumor microenvironment; Tumor-associated MSCs; Tumor-imitating cells

DOI:  https://doi.org/10.1186/s40164-024-00532-4
Res Sq. 2024 Jun 11. pii: rs.3.rs-4538031. [Epub ahead of print]

Endothelial cell Notch signaling programs cancer-associated fibroblasts to promote tumor immune evasion.

Yu Zhu, Menglan Xiang, Kevin Brulois, Nicole Lazarus, Junliang Pan, Eugene Butcher.

Stromal cells within the tumor tissue promote immune evasion as a critical strategy for cancer development and progression, but the underlying mechanisms remain poorly understood. In this study, we explore the role of endothelial cells (ECs) in the regulation of the immunosuppressive tumor microenvironment. Using mouse pancreatic ductal adenocarcinoma (PDAC) models, we found that canonical Notch signaling in endothelial cells suppresses the recruitment of antitumor T cells and promotes tumor progression by inhibiting the pro-inflammatory functions of cancer-associated fibroblasts (CAFs). Abrogation of endothelial Notch signaling modulates EC-derived angiocrine factors to enhance the pro-inflammatory activities of CAFs, which drive CXCL9/10-CXCR3-mediated T cell recruitment to inhibit tumor growth. Additionally, abrogation of endothelial Notch unleashed interferon gamma responses in the tumor microenvironment, upregulated PDL1 expression on tumor cells, and sensitized PDAC to PD1-based immunotherapy. Collectively, these data uncover a pivotal role of endothelial cells in shaping the immunosuppressive microenvironment, and suggest the potential of targeting EC-CAF interaction as a novel therapeutic modality to boost antitumor immunity.

DOI: https://doi.org/10.21203/rs.3.rs-4538031/v1
Cancer Immunol Immunother. 2024 Jul 02. 73(9): 170

Engineered CD147-CAR macrophages for enhanced phagocytosis of cancers.

Koollawat Chupradit, Saitong Muneekaew, Methichit Wattanapanitch.

  Chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematologic malignancies, but its effectiveness in solid cancers remains challenging. Macrophages are immune cells residing within the tumor microenvironment. They can phagocytose tumor cells. Recently, CAR macrophages (CAR-M) have been a promising candidate for treating solid cancers. One of the common cancer antigens overexpressed in various types of cancer is CD147. CAR-T and NK cells targeting CD147 antigen have shown significant efficacy against hepatocellular carcinoma. Nevertheless, CAR-M targeting the CD147 molecule has not been investigated. In this study, we generated CAR targeting the CD147 molecule using the THP-1 monocytic cell line (CD147 CAR-M). The CD147 CAR-M exhibited typical macrophage characteristics, including phagocytosis of zymosan bioparticles and polarization ability toward M1 and M2 phenotypes. Furthermore, the CD147 CAR-M demonstrated enhanced anti-tumor activity against K562 and MDA-MB-231 cells without exhibiting off-target cytotoxicity against normal cells. Our research provides valuable insights into the potential of CD147 CAR-M as a promising platform for cancer immunotherapy, with applications in both hematologic malignancies and solid cancers.

Keywords:  CAR-macrophages; CD147; Cancer; Chimeric antigen receptor; Immunotherapy; Phagocytosis

DOI:  https://doi.org/10.1007/s00262-024-03759-6
Cell Signal. 2024 Jun 28. pii: S0898-6568(24)00249-3. [Epub ahead of print] 111281

Metabolic crosstalk: Extracellular ATP and the tumor microenvironment in cancer progression and therapy.

Sourav Shukla, Parameswar Dalai, Reena Agrawal-Rajput.

  Adenosine 5'-triphosphate (ATP) is a vital element in energy information. It plays a critical role in transmitting signals inside the body, which is necessary for controlling the life activities of all cells, including tumor cells [1]. Its significance extends from intracellular signaling pathways to tumor regression. Purinergic signaling, a form of extracellular paracrine signaling, relies on purine nucleotides. Extracellular ectonucleotidases convert these purine nucleotides to their respective di and mono-phosphate nucleoside forms, contributing significantly to immune biology, cancer biology, and inflammation studies. ATP functions as a mighty damage-linked molecular pattern when released outside the cell, accumulating in inflammatory areas. In the tumor microenvironment (TME), purinergic receptors such as ATP-gated ion channels P2X1-5 and G protein-coupled receptors (GPCR) (P2Y) interact with ATP and other nucleotides, influencing diverse immune cell activities. CD39 and CD73-mediated extracellular ATP degradation contributes to immunosuppression by diminishing ATP-dependent activation and generating adenosine (ADO), potentially hindering antitumor immunity and promoting tumor development. Unraveling the complexities of extracellular ATP (e-ATP) and ADO effects on the TME poses challenges in identifying optimal treatment targets, yet ongoing investigations aim to devise strategies combating e-ATP/ADO-induced immunosuppression, ultimately enhancing anti-tumor immunity. This review explores e-ATP metabolism, its purinergic signaling, and therapeutic strategies targeting associated receptors and enzymes.

Keywords:  Extracellular ATP (e-ATP); Immunosuppression; Purinergic receptors; Purinergic signaling; Therapeutic potential; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.cellsig.2024.111281
Acta Biochim Biophys Sin (Shanghai). 2024 Jul 01.

Glycosylation in the tumor immune response: the bitter side of sweetness.

Yuting Cao, Wen Yi, Qiang Zhu.

  Glycosylation is the most structurally diverse form of post-translational modification (PTM) of proteins that affects a myriad of cellular processes. As a pivotal regulator of protein homeostasis, glycosylation notably impacts the function of proteins, spanning from protein localization and stability to protein-protein interactions. Aberrant glycosylation is a hallmark of cancer, and extensive studies have revealed the multifaceted roles of glycosylation in tumor growth, migration, invasion and immune escape Over the past decade, glycosylation has emerged as an immune regulator in the tumor microenvironment (TME). Here, we summarize the intricate interplay between glycosylation and the immune system documented in recent literature, which orchestrates the regulation of the tumor immune response through endogenous lectins, immune checkpoints and the extracellular matrix (ECM) in the TME. In addition, we discuss the latest progress in glycan-based cancer immunotherapy. This review provides a basic understanding of glycosylation in the tumor immune response and a theoretical framework for tumor immunotherapy.

Keywords:  endogenous lectins; extracellular matrix; glycosylation; immune checkpoint; immune response; immunotherapy

DOI:  https://doi.org/10.3724/abbs.2024107
Cancer Lett. 2024 Jul 03. pii: S0304-3835(24)00496-8. [Epub ahead of print] 217101

O-GlcNAc signaling: implications for stress-induced adaptive response pathway in the tumor microenvironment.

Yu Zhao, Renlong Li, Weizhen Wang, Haohao Zhang, Qiujin Zhang, Jialu Jiang, Ying Wang, Yan Li, Feng Guan, Yongzhan Nie.

  The tumor microenvironment (TME) consists of tumor cells, non-tumor cells, extracellular matrix, and signaling molecules, which can contribute to tumor initiation, progression, and therapy resistance. In response to starvation, hypoxia, and drug treatments, tumor cells undergo a variety of deleterious endogenous stresses, such as hypoxia, DNA damage, and oxidative stress. In this context, to survive the difficult situation, tumor cells evolve multiple conserved adaptive responses, including metabolic reprogramming, DNA damage checkpoints, homologous recombination, up-regulated antioxidant pathways, and activated unfolded protein responses. In the last decades, the protein O-GlcNAcylation has emerged as a crucial causative link between glucose metabolism and tumor progression. Here, we discuss the relevant pathways that regulate the above responses. These pathways are adaptive adjustments induced by endogenous stresses in cells. In addition, we systematically discuss the role of O-GlcNAcylation-regulated stress-induced adaptive response pathways (SARPs) in TME remodeling, tumor progression, and treatment resistance. We also emphasize targeting O-GlcNAcylation through compounds that modulate OGT or OGA activity to inhibit tumor progression. It seems that targeting O-GlcNAcylated proteins to intervene in TME may be a novel approach to improve tumor prognosis.

Keywords:  DNA replication and damage stress; Endoplasmic reticulum stress; Hypoxia; Immune activation; Metabolic stress; O-GlcNAcylation; Oxidative stress; Stress-induced adaptive response-related pathway (SARPs); Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2024.217101
J Vis Exp. 2024 Jun 14.

Generation and Functional Verification of Hypoxia-sensitive Chimeric Antigen Receptor-T Cells.

Ying Xue, Yunyu Mao, Qibin Liao, Chen Zhao, Xiaoyan Zhang, Jianqing Xu.

Extensive studies have proven the promise of chimeric antigen receptor T (CAR-T) cell therapy in treating hematological malignancies. However, treating solid tumors remains challenging, as exemplified by the safety concerns that arise when CAR-T cells attack normal cells expressing the target antigens. Researchers have explored various approaches to enhance the tumor selectivity of CAR-T cell therapy. One representative strategy along this line is the construction of hypoxia-sensitive CAR-T cells, which are designed by fusing an oxygen-dependent degradation domain to the CAR moiety and are strategized to attain high CAR expression only in a hypoxic environment-the tumor microenvironment (TME). This paper presents a protocol for the generation of such CAR-T cells and their functional characterization, including methods to analyze the changes in CAR expression and killing capacity in response to different oxygen levels established by a mobile incubator chamber. The constructed CAR-T cells are anticipated to demonstrate CAR expression and cytotoxicity in an oxygen-sensitive manner, thus supporting their capability to distinguish between hypoxic TME and normoxic normal tissues for selective activation.

DOI: https://doi.org/10.3791/66697
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 Jun;40(6): 561-565

[Research progress in macrophage migration inhibitory factor (MIF) in tumor immune response].

Xiaoqing Xie, Yaxian Liu, Junke Wang, Lixia Lu, Jinpeng Hong, Jiayu Chen, Xiaohui Yu.

Macrophage migration inhibitor factor (MIF), as a pro-inflammatory and oncogenic cytokine, is highly expressed in a variety of malignant tumors and recruits tumor cells or immune cells into the tumor microenvironment. MIF affects the development of tumor by altering the tumor microenvironment. In the process of tumor, MIF not only plays an anti-inflammatory role, but also promotes tumorigenesis by immune escape and immune tolerance.This is closely related to immune cells that play a role in the tumor immune response, mainly including natural killer (NK) cells, macrophages, dendritic cells, B cells, T cells and myeloid-derived suppressor cells. The article summarizes the role of MIF in tumor immune and the relationship between MIF and the development of malignant tumors, in order to provide new ideas and possible therapy for tumor treatment.
Oncotarget. 2023 Aug 10. 14 755-757

Inhibition of glutamine metabolism: acting on tumoral cells or on tumor microenvironment?

Raul Peña.



Keywords:  CAF; fibroblasts; glutamine; snail1; tumor microenvironment

DOI:  https://doi.org/10.18632/oncotarget.28443
Zhonghua Jie He He Hu Xi Za Zhi. 2024 Jul 12. 47(7): 668-675

[Characteristics of the tumor microenvironment and therapeutic progress in malignant pleural effusion].

S H Tan, W M Li, P W Tian.

Malignant pleural effusion (MPE) can be secondary to various advanced malignant tumors. Although systemic anti tumor therapy may be effective in primary tumors, it cannot reduce the accumulation of MPE in proportion of the patients. The interaction of tumor cells, immune cells, and mesenchymal cells, as well as the abnormal proliferation of tumor-associated blood vessels, together create an immunosuppressive microenvironment for MPE, which promotes the abnormal proliferation of tumor cells and the accumulation of MPE. With the in-depth study of the tumor microenvironment, the application of local systemic anti-tumor therapy with local intrathoracic application of immune checkpoint inhibitors, immune cells, cytokines, and gene-mediated cytotoxic immunotherapy are able to alleviate the immunosuppressive tumor microenvironment and inhibit the accumulation of MPE. This article aimed to describe the tumor microenvironment in MPE and provide clues for identifying novel therapeutic targets.

DOI: https://doi.org/10.3760/cma.j.cn112147-20240119-00039
Biochim Biophys Acta Mol Basis Dis. 2024 Jul 01. pii: S0925-4439(24)00325-9. [Epub ahead of print] 167332

Mechanistic insights into mesenchymal-amoeboid transition as an intelligent cellular adaptation in cancer metastasis and resistance.

Amir Barzegar Behrooz, Shahla Shojaei.

  Malignant cell plasticity is an important hallmark of tumor biology and crucial for metastasis and resistance. Cell plasticity lets cancer cells adapt to and escape the therapeutic strategies, which is the leading cause of cancer patient mortality. Epithelial cells acquire mobility via epithelial-mesenchymal transition (EMT), whereas mesenchymal cells enhance their migratory ability and clonogenic potential by acquiring amoeboid characteristics through mesenchymal-amoeboid transition (MAT). Tumor formation, progression, and metastasis depend on the tumor microenvironment (TME), a complex ecosystem within and around a tumor. Through increased migration and metastasis of cancer cells, the TME also contributes to malignancy. This review underscores the distinction between invasion pattern morphological manifestations and the diverse structures found within the TME. Furthermore, the mechanisms by which amoeboid-associated characteristics promote resistance and metastasis and how these mechanisms may represent therapeutic opportunities are discussed.

Keywords:  Amoeboid-mesenchymal transition; Extracellular matrix; Focal adhesion kinase; GTPase-activating protein; Guanine nucleotide exchange factor; Small GTPase

DOI:  https://doi.org/10.1016/j.bbadis.2024.167332
bioRxiv. 2024 Jun 23. pii: 2024.06.19.599651. [Epub ahead of print]

Cell of origin alters myeloid-mediated immunosuppression in lung adenocarcinoma.

Minxiao Yang, Noah Shulkin, Edgar Gonzalez, Jonathan Castillo, Chunli Yan, Keqiang Zhang, Leonidas Arvanitis, Zea Borok, W Dean Wallace, Dan Raz, Evanthia T Roussos Torres, Crystal N Marconett.

Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the tumor microenvironment is poorly understood. Lung adenocarcinoma (LUAD) arises in the distal alveolar epithelium which is populated primarily by alveolar epithelial type I (AT1) and type II (AT2) cells. It has been previously reported that Gramd2 + AT1 cells can give rise to a histologically-defined LUAD that is distinct in pathology and transcriptomic identity from that arising from Sftpc + AT2 cells 1,2 . To determine how cells of origin influence the tumor immune microenvironment (TIME) landscape, we comprehensively characterized transcriptomic, molecular, and cellular states within the TIME of Gramd2 + AT1 and Sftpc + AT2-derived LUAD using KRAS G12D oncogenic driver mouse models. Myeloid cells within the Gramd2 + AT1-derived LUAD TIME were increased, specifically, immunoreactive monocytes and tumor associated macrophages (TAMs). In contrast, the Sftpc + AT2 LUAD TIME was enriched for Arginase-1 + myeloid derived suppressor cells (MDSC) and TAMs expressing profiles suggestive of immunosuppressive function. Validation of immune infiltration was performed using flow cytometry, and intercellular interaction analysis between the cells of origin and major myeloid cell populations indicated that cell-type specific markers SFTPD in AT2 cells and CAV1 in AT1 cells mediated unique interactions with myeloid cells of the differential immunosuppressive states within each cell of origin mouse model. Taken together, Gramd2 + AT1-derived LUAD presents with an anti-tumor, immunoreactive TIME, while the TIME of Sftpc + AT2-derived LUAD has hallmarks of immunosuppression. This study suggests that LUAD cell of origin influences the composition and suppression status of the TIME landscape and may hold critical implications for patient response to immunotherapy.

DOI: https://doi.org/10.1101/2024.06.19.599651
Cancer Immunol Res. 2024 Jul 02. 12(7): 798-799

Do Not Forget the Granulocytic Compartment's Role in T cell-Mediated Antitumor Immunity.

Udo S Gaipl.

Antitumor immune responses are predominantly mediated by CD8+ cytotoxic T cells (CTLs). But immune-modulatory factors in the tumor microenvironment determine the effectiveness of these responses. In this issue, Wei and colleagues report a new role for CTL-derived IL3 in stimulating basophilic granulocytes to produce IL4, which, in turn, activates, reprograms, and stabilizes CTLs. These findings stress the importance of the crosstalk between the innate and adaptive immune systems to elicit efficient antitumor immunity. See related article by Wei et al., p. 822 (3).

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0395
Cell Rep Med. 2024 Jun 24. pii: S2666-3791(24)00330-6. [Epub ahead of print] 101626

Modulating cancer mechanopathology to restore vascular function and enhance immunotherapy.

Fotios Mpekris, Myrofora Panagi, Antonia Charalambous, Chrysovalantis Voutouri, Triantafyllos Stylianopoulos.

  Solid tumor pathology, characterized by abnormalities in the tumor microenvironment (TME), challenges therapeutic effectiveness. Mechanical factors, including increased tumor stiffness and accumulation of intratumoral forces, can determine the success of cancer treatments, defining the tumor's "mechanopathology" profile. These abnormalities cause extensive vascular compression, leading to hypoperfusion and hypoxia. Hypoperfusion hinders drug delivery, while hypoxia creates an unfavorable TME, promoting tumor progression through immunosuppression, heightened metastatic potential, drug resistance, and chaotic angiogenesis. Strategies targeting TME mechanopathology, such as vascular and stroma normalization, hold promise in enhancing cancer therapies with some already advancing to the clinic. Normalization can be achieved using anti-angiogenic agents, mechanotherapeutics, immune checkpoint inhibitors, engineered bacterial therapeutics, metronomic nanomedicine, and ultrasound sonopermeation. Here, we review the methods developed to rectify tumor mechanopathology, which have even led to cures in preclinical models, and discuss their bench-to-bedside translation, including the derivation of biomarkers from tumor mechanopathology for personalized therapy.

Keywords:  anti-angiogenic therapy; biomarkers; engineered bacteria; precision oncology; tumor normalization

DOI:  https://doi.org/10.1016/j.xcrm.2024.101626
J Family Med Prim Care. 2024 May;13(5): 1628-1635

Impact of high-salt diet in health and diseases and its role in pursuit of cancer immunotherapy by modulating gut microbiome.

Yuvaraj Balan, Raja Sundaramurthy, Archana Gaur, Sakthivadivel Varatharajan, Gerard Marshall Raj.

  Cancer chemotherapy remains an area of concern, as many of the therapies are uncomfortable involving side effects and unpleasant experiences. These factors could further reduce patient's quality of life, and even endanger their life. Many therapeutic strategies have been tried to reduce the unpleasant side effects and increase the treatment effectiveness; however, none have shown to have promising effects. One of the main hindrances to cancer therapy is the escape strategies by tumor cells to the immune attack. Promoting inflammation in the tumor microenvironment is the cornerstone and key therapeutic target in cancer chemotherapy. High-salt diet (HSD) intake, though it has deleterious effects on human health by promoting chronic inflammation, is found to be advantageous in the tumor microenvironment. Studies identified HSD favors an increased abundance of Bifidobacterium species in the tumor environment due to gut barrier alteration, which, in turn, promotes inflammation and favors improved response to cancer chemotherapy. A review of the literature was carried out to find out the effects of an HSD on health and diseases, with special mention of its effect on cancer chemotherapy. Studies emphasized HSD would block the myeloid-derived suppressor cells which will enhance the tumor immunity. Exploration of the precise mechanism of simple HSD regime/ingestion of specific bacterial species as probiotics will be effective and essential to formulate the game-changing cancer chemotherapy. With the modern era of healthcare moving toward precision medicine where the physician can choose the treatment option suitable for the individual, HSD regime/ingestion of specific bacterial species can be considered.

Keywords:  Anti-tumor activity; chronic inflammation; gut dysbiosis; high-salt diet; immuno-inflammation; tumor immunity

DOI:  https://doi.org/10.4103/jfmpc.jfmpc_1574_23
Signal Transduct Target Ther. 2024 Jul 03. 9(1): 169

Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression.

Hao Peng, Meng Yang, Kun Feng, Qingpeng Lv, Yewei Zhang.

More than 90% of hepatocellular carcinoma (HCC) cases develop in the presence of fibrosis or cirrhosis, making the tumor microenvironment (TME) of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts (CAFs) and cancer stem cells (CSCs), which collectively regulate HCC progression. However, the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain elusive. Our study unveils a significant upregulation of Sema3C in fibrotic liver, HCC tissues, peripheral blood of HCC patients, as well as sorafenib-resistant tissues and cells, with its overexpression correlating with the acquisition of stemness properties in HCC. We further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C, activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor initiation. Additionally, HCC cells-derived Sema3C facilitated extracellular matrix (ECM) contraction and collagen deposition in vivo, while also promoting the proliferation and activation of hepatic stellate cells (HSCs). Mechanistically, Sema3C interacted with NRP1 and ITGB1 in HSCs, activating downstream NF-kB signaling, thereby stimulating the release of IL-6 and upregulating HMGCR expression, consequently enhancing cholesterol synthesis in HSCs. Furthermore, CAF-secreted TGF-β1 activates AP1 signaling to augment Sema3C expression in HCC cells, establishing a positive feedback loop that accelerates HCC progression. Notably, blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo. In sum, our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CSCs and stroma during hepatocarcinogenesis, thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.

DOI: https://doi.org/10.1038/s41392-024-01887-0
Med Oncol. 2024 Jul 01. 41(8): 190

The role of histamine and its receptors in breast cancer: from pathology to therapeutic targets.

Hossein Azimi, Afifeh Jafari, Mahafarin Maralani, Homa Davoodi.

  Breast cancer is the most common malignancy in women, and despite the development of new treatment methods and the decreasing mortality rate in recent years, one of the clinical problems in breast cancer treatment is chronic inflammation in the tumor microenvironment. Histamine, an inflammatory mediator, is produced by tumor cells and can induce chronic inflammation and the growth of some tumors by recruiting inflammatory cells. It can also affect tumor physiopathology, antitumor treatment efficiency, and patient survival. Antihistamines, as histamine receptor antagonists, play a role in modulating the effects of these receptors in tumor cells and can affect some treatment methods for breast cancer therapy; in this review, we investigate the role of histamine, its receptors, and antihistamines in breast cancer pathology and treatment methods.

Keywords:  Antihistamine; Breast cancer; Histamine

DOI:  https://doi.org/10.1007/s12032-024-02437-y
Cancer Immunol Immunother. 2024 Jul 02. 73(9): 163

Impact of fludarabine and treosulfan on ovarian tumor cells and mesothelin chimeric antigen receptor T cells.

Ibrahim El-Serafi, Isabella Micallef Nilsson, Alina Moter, Zhe Duan, Jonas Mattsson, Isabelle Magalhaes.

  In addition to their immunosuppressive effect, cytostatics conditioning prior to adoptive therapy such as chimeric antigen receptor (CAR) T cells may play a role in debulking and remodeling the tumor microenvironment. We investigated in vitro the killing efficacy and impact of treosulfan and fludarabine on ovarian cancer cells expressing mesothelin (MSLN) and effect on MSLN-targeting CAR T cells. Treosulfan and fludarabine had a synergetic effect on killing of SKOV3 and OVCAR4 cells. Sensitivity to the combination of treosulfan and fludarabine was increased when SKOV3 cells expressed MSLN and when OVCAR4 cells were tested in hypoxia, while MSLN cells surface expression by SKOV3 and OVCAR4 cells was not altered after treosulfan or fludarabine exposure. Exposure to treosulfan or fludarabine (10 µM) neither impacted MSLN-CAR T cells degranulation, cytokines production upon challenge with MSLN + OVCAR3 cells, nor induced mitochondrial defects. Combination of treosulfan and fludarabine decreased MSLN-CAR T cells anti-tumor killing in normoxia but not hypoxia. In conclusion, treosulfan and fludarabine killed MSLN + ovarian cancer cells without altering MSLN-CAR T cells functions (at low cytostatics concentration) even in hypoxic conditions, and our data support the use of treosulfan and fludarabine as conditioning drugs prior to MSLN-CAR T cell therapy.

Keywords:  CAR T cell; Fludarabine; Mesothelin; Ovarian cancer; Treosulfan

DOI:  https://doi.org/10.1007/s00262-024-03740-3
J Steroid Biochem Mol Biol. 2024 Jun 29. pii: S0960-0760(24)00123-7. [Epub ahead of print] 106575

Glucocorticoid Receptors Orchestrate a Convergence of Host and Cellular Stress Signals in Triple Negative Breast Cancer.

Sai Harshita Posani, Noelle E Gillis, Carol A Lange.

  Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of the nuclear steroid receptors that bind estrogens (ER) and progestogens (PRs) and does not exhibit HER2 (Human epidermal growth factor 2) receptor overexpression. Even in the face of initially effective chemotherapies, TNBC patients often relapse. One primary cause for therapy-resistant tumor progression is the activation of cellular stress signaling pathways. The glucocorticoid receptor (GR), a corticosteroid-activated transcription factor most closely related to PR, is a mediator of both endocrine/host stress and local tumor microenvironment (TME)-derived and cellular stress responses. Interestingly, GR expression is associated with a good prognosis in ER+ breast cancer but predicts poor prognosis in TNBC. Classically, GR's transcriptional activity is regulated by circulating glucocorticoids. Additionally, GR is regulated by ligand-independent signaling events. Notably, the stress-activated protein kinase, p38 MAP kinase, phosphorylates GR at serine 134 (Ser134) in response to TME-derived growth factors and cytokines, including HGF and TGFβ1. Phospho-Ser134-GR (p-Ser134-GR) associates with cytoplasmic and nuclear signaling molecules, including 14-3-3ζ, aryl hydrocarbon receptors (AhR), and hypoxia-inducible factors (HIFs). Phospho-GR/HIF-containing transcriptional complexes upregulate gene sets whose protein products include the components of inducible oncogenic signaling pathways (PTK6) that further promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC. Recent studies have implicated liganded p-Ser134-GR (p-GR) in dexamethasone-mediated upregulation of genes related to TNBC cell motility and dysregulated metabolism. Herein, we review the tumor-promoting roles of GR and discuss how both ligand-dependent and ligand-independent/stress signaling-driven inputs to p-GR converge to orchestrate metastatic TNBC progression.

Keywords:  glucocorticoids; steroid receptors; stress signaling; triple negative breast cancer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.jsbmb.2024.106575
Eur J Med Res. 2024 Jul 05. 29(1): 357

M2-type tumor-associated macrophages upregulated PD-L1 expression in cervical cancer via the PI3K/AKT pathway.

Fan Guo, Weina Kong, Dewei Li, Gang Zhao, Miyessar Anwar, Feifei Xia, Yuanming Zhang, Cailing Ma, Xiumin Ma.

  BACKGROUND AND PURPOSE: PD-1/PD-L1 inhibitors have become a promising therapy. However, the response rate is lower than 30% in patients with cervical cancer (CC), which is related to immunosuppressive components in tumor microenvironment (TME). Tumor-associated macrophages (TAMs), as one of the most important immune cells, are involved in the formation of tumor suppressive microenvironment. Therefore, it will provide a theoretical basis for curative effect improvement about the regulatory mechanism of TAMs on PD-L1 expression.METHODS: The clinical data and pathological tissues of CC patients were collected, and the expressions of PD-L1, CD68 and CD163 were detected by immunohistochemistry. Bioinformatics was used to analyze the macrophage subtypes involved in PD-L1 regulation. A co-culture model was established to observe the effects of TAMs on the morphology, migration and invasion function of CC cells, and the regulatory mechanism of TAMs on PD-L1.
RESULTS: PD-L1 expression on tumor cells could predict the poor prognosis of patients. And there was a strong correlation between PD-L1 expression with CD163+TAMs infiltration. Similarly, PD-L1 expression was associated with M1/M2-type TAMs infiltration in bioinformatics analysis. The results of cell co-culture showed that M1/M2-type TAMs could upregulate PD-L1 expression, especially M2-type TAMs may elevate the PD-L1 expression via PI3K/AKT pathway. Meanwhile, M1/M2-type TAMs can affect the morphological changes, and enhance migration and invasion abilities of CC cells.
CONCLUSIONS: PD-L1 expression in tumor cells can be used as a prognostic factor and is closely related to CD163+TAMs infiltration. In addition, M2-type TAMs can upregulate PD-L1 expression in CC cells through PI3K/AKT pathway, enhance the migration and invasion capabilities, and affect the tumor progression.

Keywords:  Cervical cancer; Prognosis; Tumor microenvironment (TME); Tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.1186/s40001-024-01897-2
Cancer Lett. 2024 Jun 28. pii: S0304-3835(24)00485-3. [Epub ahead of print] 217090

Binding of interleukin-1 receptor antagonist to cholinergic receptor muscarinic 4 promotes immunosuppression and neuroendocrine differentiation in prostate cancer.

Yen-Nien Liu, Ming-Kun Liu, Yu-Ching Wen, Chien-Hsiu Li, Hsiu-Lien Yeh, Phan Vu Thuy Dung, Kuo-Ching Jiang, Wei-Hao Chen, Han-Ru Li, Jiaoti Huang, Wei-Yu Chen.

  The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.

Keywords:  Androgen deprivation therapy; CHRM4; IL1RN; neuroendocrine differentiation; tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2024.217090
Nat Rev Cancer. 2024 Jul 05.

Towards targeting the breast cancer immune microenvironment.

Michael A Harris, Peter Savas, Balaji Virassamy, Megan M R O'Malley, Jasmine Kay, Scott N Mueller, Laura K Mackay, Roberto Salgado, Sherene Loi.

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, it is also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology.

DOI: https://doi.org/10.1038/s41568-024-00714-6
FASEB J. 2024 Jul 15. 38(13): e23785

Mechanisms of triple-negative breast cancer extravasation: Impact of the physical environment and endothelial glycocalyx.

Chinedu C Okorafor, Sanjana Shastri, Ke Wen, Eno E Ebong.

  Cancer metastasis is the leading cause of death for those afflicted with cancer. In cancer metastasis, the cancer cells break off from the primary tumor, penetrate nearby blood vessels, and attach and extravasate out of the vessels to form secondary tumors at distant organs. This makes extravasation a critical step of the metastatic cascade. Herein, with a focus on triple-negative breast cancer, the role that the prospective secondary tumor microenvironment's mechanical properties play in circulating tumor cells' extravasation is reviewed. Specifically, the effects of the physically regulated vascular endothelial glycocalyx barrier element, vascular flow factors, and subendothelial extracellular matrix mechanical properties on cancer cell extravasation are examined. The ultimate goal of this review is to clarify the physical mechanisms that drive triple-negative breast cancer extravasation, as these mechanisms may be potential new targets for anti-metastasis therapy.

Keywords:  cancer cell extravasation; endothelial cells; extracellular matrix; glycocalyx; tissue stiffness; vascular flow

DOI:  https://doi.org/10.1096/fj.202400380R
Cell Mol Gastroenterol Hepatol. 2024 Jul 03. pii: S2352-345X(24)00132-2. [Epub ahead of print] 101377

DDR2/STAT3 positive feedback loop mediates the immunosuppressive microenvironment by upregulating PD-L1 and recruiting MDSCs in oxaliplatin-resistant HCC.

Wenfeng Liu, Feng Zhang, Bing Quan, Fan Yao, Rongxin Chen, Zhenggang Ren, Ling Dong, Xin Yin.

  BACKGROUND & AIMS: Transcriptome sequencing revealed high expression of discoidin domain receptor 2 (DDR2) in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study aimed to explore the role of DDR2 in oxaliplatin resistance and immune evasion in HCC.METHODS: Oxaliplatin-resistant HCC cell lines were established. The interaction between DDR2 and STAT3 was investigated, along with the mechanisms involved in DDR2/STAT3-mediated PD-L1 upregulation and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) accumulation both in vitro and in vivo.
RESULTS: DDR2 was found to induce the phosphorylation of STAT3, leading to its nuclear translocation. Conversely, the activation of STAT3 enhanced DDR2 expression. A positive feedback loop involving DDR2/STAT3 was identified in oxaliplatin-resistant HCC, associated with PD-L1 upregulation and PMN-MDSCs accumulation was identified in oxaliplatin-resistant HCC. Knockdown of DDR2 and STAT3 sensitized oxaliplatin-resistant HCC cells to oxaliplatin and resulted in decreased PMN-MDSCs and increased CD8+ T cells in the tumor microenvironment. ELISA array and MDSC transwell migration assays indicated that oxaliplatin-resistant HCC cells recruited PMN-MDSCs through CCL20. Dual luciferase reporter assays demonstrated that STAT3 can directly enhance the transcription of PD-L1 and CCL20. Furthermore, treatment with a PD-L1 antibody in combination with CCL20 blockade had significant antitumor effects on oxaliplatin-resistant HCC.
CONCLUSIONS: Our findings revealed a positive feedback mechanism involving DDR2 and STAT3 that mediates the immunosuppressive microenvironment and promotes oxaliplatin resistance and immune evasion via PD-L1 upregulation and PMN-MDSCs recruitment. Targeting the DDR2/STAT3 pathway may be a promising therapeutic strategy to overcome immune escape and chemoresistance in HCC.

Keywords:  DDR2; MDSCs; PD-L1 upregulation; STAT3; hepatocellular carcinoma

DOI:  https://doi.org/10.1016/j.jcmgh.2024.101377
J Immunother Cancer. 2024 Jul 04. pii: e008434. [Epub ahead of print]12(7):

Genetically engineering glycolysis in T cells increases their antitumor function.

Raphaëlle Toledano Zur, Orna Atar, Tilda Barliya, Shiran Hoogi, Ifat Abramovich, Eyal Gottlieb, Noga Ron-Harel, Cyrille J Cohen.

  BACKGROUND: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.METHODS: Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction with Glucose transporter 3, a glucose transporter. We co-expressed these, along with tumor-specific chimeric antigen or T-cell receptors.
RESULTS: Engineered cells demonstrated an increased cytokine secretion and upregulation of T-cell activation markers compared with control cells. Moreover, they displayed superior glycolytic capacity, which translated into an improved in vivo therapeutic potential in a xenograft model of human tumors.
CONCLUSION: In summary, these findings support the implementation of T-cell metabolic engineering to enhance the efficacy of cellular immunotherapies for cancer.

Keywords:  Immunotherapy; Receptors, Antigen; T-Lymphocytes

DOI:  https://doi.org/10.1136/jitc-2023-008434
Front Immunol. 2024 ;15 1362120

Modulatory effects of cancer stem cell-derived extracellular vesicles on the tumor immune microenvironment.

Xinyu Li, Cuilian Zhang, Wei Yue, Yuening Jiang.

  Cancer stem cells (CSCs), accounting for only a minor cell proportion (< 1%) within tumors, have profound implications in tumor initiation, metastasis, recurrence, and treatment resistance due to their inherent ability of self-renewal, multi-lineage differentiation, and tumor-initiating potential. In recent years, accumulating studies indicate that CSCs and tumor immune microenvironment act reciprocally in driving tumor progression and diminishing the efficacy of cancer therapies. Extracellular vesicles (EVs), pivotal mediators of intercellular communications, build indispensable biological connections between CSCs and immune cells. By transferring bioactive molecules, including proteins, nucleic acids, and lipids, EVs can exert mutual influence on both CSCs and immune cells. This interaction plays a significant role in reshaping the tumor immune microenvironment, creating conditions favorable for the sustenance and propagation of CSCs. Deciphering the intricate interplay between CSCs and immune cells would provide valuable insights into the mechanisms of CSCs being more susceptible to immune escape. This review will highlight the EV-mediated communications between CSCs and each immune cell lineage in the tumor microenvironment and explore potential therapeutic opportunities.

Keywords:  cancer stem cells; exosomes; extracellular vesicles; immune cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1362120
Eur J Pharmacol. 2024 Jun 27. pii: S0014-2999(24)00475-8. [Epub ahead of print] 176787

Tumoral EIF4EBP1 regulates the crosstalk between tumor-associated macrophages and tumor cells in MRTK.

Xin Wu, Tao Mi, Liming Jin, Chunnian Ren, Jinkui Wang, Zhaoxia Zhang, Jiayan Liu, Zhaoyin Wang, Peng Guo, Dawei He.

  Malignant renal rhabdoid tumor (MRTK) is an aggressive and rare malignancy primarily affecting infants and young children. The intricate interactions within the Tumor Microenvironment (TME) are crucial in shaping MRTK's progression. This study elucidates the significance of tumor-associated macrophages(TAMs) within this milieu and their interplay with eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) in tumor cells, collectively contributing to MRTK's malignant advancement. Through comprehensive analysis of clinical samples and the TARGET database, EIF4EBP1 emerges as a central macrophage-associated gene with robust prognostic implications. Elevated EIF4EBP1 expression correlates with poor prognosis and heightened infiltration of TAMs. Functional validation demonstrates that EIF4EBP1 knockdown in G401 cells significantly attenuates self-proliferation, migration, and invasion. Moreover, EIF4EBP1 regulates macrophage recruitment and M2 polarization through the ERK/P38 MAPK-MIF axis. Notably, M2 macrophages reciprocally foster the malignant behavior of MRTK tumor cells. This study unveils the pivotal role of EIF4EBP1 in propelling MRTK's malignant progression, unraveling a complex regulatory network involving EIF4EBP1 and TAMs. These findings underscore EIF4EBP1 as a promising biomarker and highlight its therapeutic potential in MRTK management.

Keywords:  EIF4EBP1; MRTK; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ejphar.2024.176787
Front Mol Biosci. 2024 ;11 1340024

Heterogeneity of cancer-associated fibroblasts and tumor-promoting roles in head and neck squamous cell carcinoma.

Imane El Herch, Stian Tornaas, Harsh Nitin Dongre, Daniela Elena Costea.

  Tumor microenvironment (TME) in head and neck squamous cell carcinoma (HNSCC) has a major influence on disease progression and therapy response. One of the predominant stromal cell types in the TME of HNSCC is cancer-associated fibroblasts (CAF). CAF constitute a diverse cell population and we are only at the beginning of characterizing and understanding the functions of various CAF subsets. CAF have been shown to interact with tumor cells and other components of the TME to shape mainly a favourable microenvironment for HNSCC progression, although some studies report existence of tumor-restraining CAF subtypes. The numerous pathways used by CAF to promote tumorigenesis may represent potential therapeutic targets. This review summarizes current knowledge on the origins, subtypes and mechanisms employed by CAF in HNSCC. The aim is to contribute to the understanding on how CAF actively influence the TME and modulate different immune cell types, as well as cancer cells, to establish a conducive setting for cancer growth. Although CAF are currently a promising therapeutic target for the treatment of other types of cancer, there is no significant therapeutic advancement in HNSCC.

Keywords:  cancer-associated fibroblasts; head and neck squamous cell carcinoma; heterogeneity; therapeutic targeting; tumor microenvironment

DOI:  https://doi.org/10.3389/fmolb.2024.1340024