bims-flamet 2024-08-04 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–08–04
twenty-six papers selected by
Peio Azcoaga, Biodonostia HRI

Cancer cell targeting by CAR-T cells: A matter of stemness.
Decoding the spatiotemporal heterogeneity of tumor-associated macrophages.
Lymphocyte homing and recirculation with tumor tertiary lymphoid structure formation: predictions for successful cancer immunotherapy.
Neutrophils' dual role in cancer: from tumor progression to immunotherapeutic potential.
High-motility pro-tumorigenic monocytes drive macrophage enrichment in the tumor microenvironment.
The role of mesenchymal stem cells in cancer and prospects for their use in cancer therapeutics.
The significant role of amino acid metabolic reprogramming in cancer.
Mechanisms of lymphoma-stromal interactions focusing on tumor-associated macrophages, fibroblastic reticular cells, and follicular dendritic cells.
CTHRC1+ fibroblasts and SPP1+ macrophages synergistically contribute to pro-tumorigenic tumor microenvironment in pancreatic ductal adenocarcinoma.
Epigenetic regulation of the tumor microenvironment: A leading force driving pancreatic cancer.
N-linked glycosylation of PD-L1/PD-1: an emerging target for cancer diagnosis and treatment.
PTGR1-mediated immune evasion mechanisms in late-stage triple-negative breast cancer: mechanisms of M2 macrophage infiltration and CD8+ T cell suppression.
Hyperactive DCs redirect aged anti-tumor immunity.
Targeting the tumor microenvironment to improve clinical outcomes in triple negative breast cancer patients and bridge the current disparity gap.
How neutrophils shape the immune response of triple-negative breast cancer: Novel therapeutic strategies targeting neutrophil extracellular traps.
S100A10 promotes cancer metastasis via recruitment of MDSCs within the lungs.
Extracellular vesicles and cancer stem cells: a deadly duo in tumor progression.
Pericytes: jack-of-all-trades in cancer-related inflammation.
Tumor-derived mitochondrial formyl peptides suppress tumor immunity through modification of the tumor microenvironment.
Systematic Analysis of Human Colorectal Cancer scRNA-seq Revealed Limited Pro-tumoral IL-17 Production Potential in Gamma Delta T Cells.
Tumor-derived GLI1 promotes remodeling of the immune tumor microenvironment in melanoma.
Editorial: CAR T-cells: novel therapeutic approaches in the new era of cancer immunotherapy.
Localized in vivo gene editing of murine cancer-associated fibroblasts.
Immune checkpoint inhibitors targeting PD-1/PD-L1 in the treatment of human lymphomas.
Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression.
Trained immunity inducers in cancer immunotherapy.

Front Mol Med. 2022 ;2 1055028

Cancer cell targeting by CAR-T cells: A matter of stemness.

Caterina D'Accardo, Gaetana Porcelli, Laura Rosa Mangiapane, Chiara Modica, Vincenzo Davide Pantina, Narges Roozafzay, Simone Di Franco, Miriam Gaggianesi, Veronica Veschi, Melania Lo Iacono, Matilde Todaro, Alice Turdo, Giorgio Stassi.

  Chimeric antigen receptor (CAR)-T cell therapy represents one of the most innovative immunotherapy approaches. The encouraging results achieved by CAR-T cell therapy in hematological disorders paved the way for the employment of CAR engineered T cells in different types of solid tumors. This adoptive cell therapy represents a selective and efficacious approach to eradicate tumors through the recognition of tumor-associated antigens (TAAs). Binding of engineered CAR-T cells to TAAs provokes the release of several cytokines, granzyme, and perforin that ultimately lead to cancer cells elimination and patient's immune system boosting. Within the tumor mass a subpopulation of cancer cells, known as cancer stem cells (CSCs), plays a crucial role in drug resistance, tumor progression, and metastasis. CAR-T cell therapy has indeed been exploited to target CSCs specific antigens as an effective strategy for tumor heterogeneity disruption. Nevertheless, a barrier to the efficacy of CAR-T cell-based therapy is represented by the poor persistence of CAR-T cells into the hostile milieu of the CSCs niche, the development of resistance to single targeting antigen, changes in tumor and T cell metabolism, and the onset of severe adverse effects. CSCs resistance is corroborated by the presence of an immunosuppressive tumor microenvironment (TME), which includes stromal cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and immune cells. The relationship between TME components and CSCs dampens the efficacy of CAR-T cell therapy. To overcome this challenge, the double strategy based on the use of CAR-T cell therapy in combination with chemotherapy could be crucial to evade immunosuppressive TME. Here, we summarize challenges and limitations of CAR-T cell therapy targeting CSCs, with particular emphasis on the role of TME and T cell metabolic demands.

Keywords:  CAR-T cell therapy; anti-cancer therapy; cancer stem cells; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fmmed.2022.1055028
Mol Cancer. 2024 Jul 27. 23(1): 150

Decoding the spatiotemporal heterogeneity of tumor-associated macrophages.

Xiangyuan Chu, Yu Tian, Chao Lv.

  Tumor-associated macrophages (TAMs) are pivotal in cancer progression, influencing tumor growth, angiogenesis, and immune evasion. This review explores the spatial and temporal heterogeneity of TAMs within the tumor microenvironment (TME), highlighting their diverse subtypes, origins, and functions. Advanced technologies such as single-cell sequencing and spatial multi-omics have elucidated the intricate interactions between TAMs and other TME components, revealing the mechanisms behind their recruitment, polarization, and distribution. Key findings demonstrate that TAMs support tumor vascularization, promote epithelial-mesenchymal transition (EMT), and modulate extracellular matrix (ECM) remodeling, etc., thereby enhancing tumor invasiveness and metastasis. Understanding these complex dynamics offers new therapeutic targets for disrupting TAM-mediated pathways and overcoming drug resistance. This review underscores the potential of targeting TAMs to develop innovative cancer therapies, emphasizing the need for further research into their spatial characteristics and functional roles within the TME.

Keywords:  Cancer immunotherapy; Drug resistance; Spatial multiomics; Tumor microenvironment (TME); Tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.1186/s12943-024-02064-1
Front Immunol. 2024 ;15 1403578

Lymphocyte homing and recirculation with tumor tertiary lymphoid structure formation: predictions for successful cancer immunotherapy.

Weihong Tian, Wangzhi Wei, Gaofeng Qin, Xuanwen Bao, Xuecheng Tong, Min Zhou, Yuan Xue, Yu Zhang, Qixiang Shao.

  The capacity of lymphocytes continuously home to lymphoid structures is remarkable for cancer immunosurveillance and immunotherapy. Lymphocyte homing and recirculation within the tumor microenvironment (TME) are now understood to be adaptive processes that are regulated by specialized cytokines and adhesion molecule signaling cascades. Restricted lymphocyte infiltration and recirculation have emerged as key mechanisms contributing to poor responses in cancer immunotherapies like chimeric antigen receptor (CAR)-T cell therapy and immune checkpoint blockades (ICBs). Uncovering the kinetics of lymphocytes in tumor infiltration and circulation is crucial for improving immunotherapies. In this review, we discuss the current insights into the adhesive and migrative molecules involved in lymphocyte homing and transmigration. The potential mechanisms within the TME that restrain lymphocyte infiltration are also summarized. Advanced on these, we outline the determinates for tertiary lymphoid structures (TLSs) formation within tumors, placing high expectations on the prognostic values of TLSs as therapeutic targets in malignancies.

Keywords:  C-X-C chemokines; adhesion; dendritic cells; immunotherapy; lymphocyte homing; tertiary lymphoid structures

DOI:  https://doi.org/10.3389/fimmu.2024.1403578
Int Immunopharmacol. 2024 Jul 30. pii: S1567-5769(24)01309-2. [Epub ahead of print]140 112788

Neutrophils' dual role in cancer: from tumor progression to immunotherapeutic potential.

Gujie Wu, Binyang Pan, Haochu Shi, Yanjun Yi, Xiaobin Zheng, Huiyun Ma, Mengnan Zhao, Zhenshan Zhang, Lin Cheng, Yiwei Huang, Weigang Guo.

  The tumor microenvironment (TME) is intricately associated with cancer progression, characterized by dynamic interactions among various cellular and molecular components that significantly impact the carcinogenic process. Notably, neutrophils play a crucial dual role in regulating this complex environment. These cells oscillate between promoting and inhibiting tumor activity, responding to a multitude of cytokines, chemokines, and tumor-derived factors. This response modulates immune reactions and affects the proliferation, metastasis, and angiogenesis of cancer cells. A significant aspect of their influence is their interaction with the endoplasmic reticulum (ER) stress responses in cancer cells, markedly altering tumor immunodynamics by modulating the phenotypic plasticity and functionality of neutrophils. Furthermore, neutrophil extracellular traps (NETs) exert a pivotal influence in the progression of malignancies by enhancing inflammation, metastasis, immune suppression, and thrombosis, thereby exacerbating the disease. In the realm of immunotherapy, checkpoint inhibitors targeting PD-L1/PD-1 and CTLA-4 among others have underscored the significant role of neutrophils in enhancing therapeutic responses. Recent research has highlighted the potential of using neutrophils for targeted drug delivery through nanoparticle systems, which precisely control drug release and significantly enhance antitumor efficacy. This review thoroughly examines the diverse functions of neutrophils in cancer treatment, emphasizing their potential in regulating immune therapy responses and as drug delivery carriers, offering innovative perspectives and profound implications for the development of targeted diagnostic and therapeutic strategies in oncology.

Keywords:  Drug delivery; Endoplasmic reticulum; Immunotherapy; Neutrophil extracellular traps; Neutrophils; The tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2024.112788
bioRxiv. 2024 Jul 18. pii: 2024.07.16.603739. [Epub ahead of print]

High-motility pro-tumorigenic monocytes drive macrophage enrichment in the tumor microenvironment.

Wenxuan Du, Bryan Zhou, André Forjaz, Sarah M Shin, Fan Wu, Ashleigh J Crawford, Praful R Nair, Adrian C Johnston, Hoku West-Foyle, Ashley Tang, Dongjoo Kim, Rong Fan, Ashley L Kiemen, Pei-Hsun Wu, Jude M Phillip, Won Jin Ho, David E Sanin, Denis Wirtz.

Enrichment of tumor-associated macrophages (TAMΦs) in the tumor microenvironment correlates with worse clinical outcomes in triple-negative breast cancer (TNBC) patients, prompting the development of therapies to inhibit TAMΦ infiltration. However, the lackluster efficacy of CCL2-based chemotaxis blockade in clinical trials suggests that a new understanding of monocyte/macrophage infiltration may be necessary. Here we demonstrate that random migration, and not only chemotaxis, drives macrophage tumor infiltration. We identified tumor- associated monocytes (TAMos) that display a dramatically enhanced migration capability, induced rapidly by the tumor microenvironment, that drives effective tumor infiltration, in contrast to low-motility differentiated macrophages. TAMo, not TAMΦ, promotes cancer cell proliferation through activation of the MAPK pathway. IL-6 secreted both by cancer cells and TAMo themselves enhances TAMo migration by increasing dendritic protrusion dynamics and myosin- based contractility via the JAK2/STAT3 signaling pathway. Independent from CCL2 mediated chemotaxis, IL-6 driven enhanced migration and pro-proliferative effect of TAMo were validated in a syngeneic TNBC mouse model. Depletion of IL-6 in cancer cells significantly attenuated monocyte infiltration and reversed TAMo-induced cancer cell proliferation. This work reveals the critical role random migration plays in monocyte driven TAMΦ enrichment in a tumor and pinpoints IL-6 as a potential therapeutic target in combination with CCL2 to ameliorate current strategies against TAMΦ infiltration.

DOI: https://doi.org/10.1101/2024.07.16.603739
MedComm (2020). 2024 Aug;5(8): e663

The role of mesenchymal stem cells in cancer and prospects for their use in cancer therapeutics.

Jian Tang, Yu Chen, Chunhua Wang, Ying Xia, Tingyu Yu, Mengjun Tang, Kun Meng, Lijuan Yin, Yang Yang, Liang Shen, Hui Xing, Xiaogang Mao.

  Mesenchymal stem cells (MSCs) are recruited by malignant tumor cells to the tumor microenvironment (TME) and play a crucial role in the initiation and progression of malignant tumors. This role encompasses immune evasion, promotion of angiogenesis, stimulation of cancer cell proliferation, correlation with cancer stem cells, multilineage differentiation within the TME, and development of treatment resistance. Simultaneously, extensive research is exploring the homing effect of MSCs and MSC-derived extracellular vesicles (MSCs-EVs) in tumors, aiming to design them as carriers for antitumor substances. These substances are targeted to deliver antitumor drugs to enhance drug efficacy while reducing drug toxicity. This paper provides a review of the supportive role of MSCs in tumor progression and the associated molecular mechanisms. Additionally, we summarize the latest therapeutic strategies involving engineered MSCs and MSCs-EVs in cancer treatment, including their utilization as carriers for gene therapeutic agents, chemotherapeutics, and oncolytic viruses. We also discuss the distribution and clearance of MSCs and MSCs-EVs upon entry into the body to elucidate the potential of targeted therapies based on MSCs and MSCs-EVs in cancer treatment, along with the challenges they face.

Keywords:  drug delivery; mesenchymal stem cells; tumor microenvironment; tumor‐targeted therapy

DOI:  https://doi.org/10.1002/mco2.663
Cell Commun Signal. 2024 Jul 29. 22(1): 380

The significant role of amino acid metabolic reprogramming in cancer.

Xiaohong Liu, Bo Ren, Jie Ren, Minzhi Gu, Lei You, Yupei Zhao.

  Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.

Keywords:  Amino acid metabolism; Angiogenesis; Epigenetic regulation; Immune tolerance; Redox; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-024-01760-1
J Clin Exp Hematop. 2024 Jul 31.

Mechanisms of lymphoma-stromal interactions focusing on tumor-associated macrophages, fibroblastic reticular cells, and follicular dendritic cells.

Rintaro Ohe.

  The interaction between cancer cells and stromal cells contributes to the pathogenesis of various types of tumors in the tumor microenvironment (TME). Macrophages (Mφs), a type of stromal cell, are transformed into tumor-associated Mφs (TAMs) after integrating within solid tumors. TAMs are known to interact with cancer cells and induce tumor progression. Thus, the cancer cells construct an organ-specific TME, which is advantageous for the survival of cancer cells in the TME. The density of stromal cells is known to be involved in the prognosis of patients with lymphomas. A higher density of stromal cells increases the interaction between lymphoma cells and stromal cells, promoting lymphoma progression. This review focuses on stromal cells in lymphoid tissues, such as TAMs, fibroblastic reticular cells (FRCs), and follicular dendritic cells (FDCs). This review also focuses on the signal transduction caused by stromal cells and tumor cells via factors such as cytokines. IL-10 and other cytokines secreted by TAMs activate the JAK/STAT pathway in lymphoma cells of follicular lymphoma, classic Hodgkin lymphoma, and diffuse large B-cell lymphoma. FRCs play roles in tumor promotion in follicular lymphoma and diffuse large B-cell lymphoma. Cytokines/chemokines secreted by FDCs play essential roles in lymphoma cell survival, proliferation, invasion, and migration in follicular lymphoma. In conclusion, TAMs, FRCs, and FDCs play crucial roles in the TME of lymphomas. Furthermore, histological spatial analysis revealing the positional relationship of each cell could highlight lymphoma-stromal interactions.

Keywords:  fibroblastic reticular cell; follicular dendritic cell; histological spatial analysis; lymphoma-stromal interaction; tumor-associated macrophage

DOI:  https://doi.org/10.3960/jslrt.24034
Sci Rep. 2024 Jul 29. 14(1): 17412

CTHRC1+ fibroblasts and SPP1+ macrophages synergistically contribute to pro-tumorigenic tumor microenvironment in pancreatic ductal adenocarcinoma.

Evan Li, Hoi Ching Zoey Cheung, Shuangge Ma.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer that accounts for over 90% of all pancreatic cancer cases. With a 5-year survival rate of only 13%, PDAC has proven to be extremely desmoplastic and immunosuppressive to most current therapies, including chemotherapy and surgical resection. In recent years, focus has shifted to understanding the tumor microenvironment (TME) around PDAC, enabling a greater understanding of biological pathways and intercellular interactions that can ultimately lead to potential for future drug targets. In this study, we leverage a combination of single-cell and spatial transcriptomics to further identify cellular populations and interactions within the highly heterogeneous TME. We demonstrate that SPP1+APOE+ tumor-associated macrophages (TAM) and CTHRC1+GREM1+ cancer-associated myofibroblasts (myCAF) not only act synergistically to promote an immune-suppressive TME through active extracellular matrix (ECM) deposition and epithelial mesenchymal transition (EMT), but are spatially colocalized and correlated, leading to worse prognosis. Our results highlight the crosstalk between stromal and myeloid cells as a significant area of study for future therapeutic targets to treat cancer.

DOI: https://doi.org/10.1038/s41598-024-68109-z
Pancreatology. 2024 Jul 15. pii: S1424-3903(24)00685-9. [Epub ahead of print]

Epigenetic regulation of the tumor microenvironment: A leading force driving pancreatic cancer.

Renzo Vera, María Julia Lamberti, Alina L Gonzalez, Martín E Fernandez-Zapico.

  Dysregulation of the epigenomic landscape of tumor cells has been implicated in the pathogenesis of pancreatic cancer. However, these alterations are not only restricted to neoplastic cells. The behavior of other cell populations in the tumor stroma such as cancer-associated fibroblasts, immune cells, and others are mostly regulated by epigenetic pathways. Here, we present an overview of the main cellular and acellular components of the pancreatic cancer tumor microenvironment and discuss how the epigenetic mechanisms operate at different levels in the stroma to establish a differential gene expression to regulate distinct cellular phenotypes contributing to pancreatic tumorigenesis.

Keywords:  Epigenetics; Gene expression; Pancreatic cancer; Stroma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.pan.2024.07.005
J Transl Med. 2024 Jul 30. 22(1): 705

N-linked glycosylation of PD-L1/PD-1: an emerging target for cancer diagnosis and treatment.

Zhiyun Duan, Runhan Shi, Bo Gao, Jiabin Cai.

  During tumorigenesis and progression, the immune checkpoint programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) play critical roles in suppressing T cell-mediated anticancer immune responses, leading to T-cell exhaustion and subsequent tumor evasion. Therefore, anti-PD-L1/PD-1 therapy has been an attractive strategy for treating cancer over the past decade. However, the overall efficacy of this approach remains suboptimal, revealing an urgent need for novel insights. Interestingly, increasing evidence indicates that both PD-L1 on tumor cells and PD-1 on tumor-specific T cells undergo extensive N-linked glycosylation, which is essential for the stability and interaction of these proteins, and this modification promotes tumor evasion. In various preclinical models, targeting the N-linked glycosylation of PD-L1/PD-1 was shown to significantly increase the efficacy of PD-L1/PD-1 blockade therapy. Furthermore, deglycosylation of PD-L1 strengthens the signal intensity in PD-L1 immunohistochemistry (IHC) assays, improving the diagnostic and therapeutic relevance of this protein. In this review, we provide an overview of the regulatory mechanisms underlying the N-linked glycosylation of PD-L1/PD-1 as well as the crucial role of N-linked glycosylation in PD-L1/PD-1-mediated immune evasion. In addition, we highlight the promising implications of targeting the N-linked glycosylation of PD-L1/PD-1 in the clinical diagnosis and treatment of cancer. Our review identifies knowledge gaps and sheds new light on the cancer research field.

Keywords:  Clinical diagnosis; Immune evasion; Immunotherapy; N-linked glycosylation; PD-1; PD-L1

DOI:  https://doi.org/10.1186/s12967-024-05502-2
Apoptosis. 2024 Jul 28.

PTGR1-mediated immune evasion mechanisms in late-stage triple-negative breast cancer: mechanisms of M2 macrophage infiltration and CD8+ T cell suppression.

Fang Huang, Fuhe Wang, Qilu Hu, Ying Li, Da Jiang.

  Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by metabolic dysregulation. Tumor cell immune escape plays an indispensable role in the development of TNBC tumors. Furthermore, in the abstract, we explicitly mention the techniques used and enhance the clarity and impact of our findings. "Based on bioinformatics analysis results, we utilized CRISPR/Cas9 technology to knockout the target gene and established a mouse model of breast cancer. Through experiments such as CCK8, scratch assay, and Transwell assay, we further investigated the impact of target gene knockout on the malignant behavior of tumor cells. Subsequently, we conducted immunohistochemistry and Western Blot experiments to study the expression of macrophage polarization and infiltration-related markers and evaluate the effect of the target gene on macrophage polarization. Next, through co-culture experiments, we simulated the tumor microenvironment and used immunohistochemistry staining to observe and analyze the distribution and activation status of M2 macrophages and CD8+ T cells in the co-culture system. We validated in vivo experiments the molecular mechanism by which the target gene regulates immune cell impact on TNBC progression.

Keywords:  CD8+ T cells; Immune evasion; M2 macrophages; PD-L1; PTGR1; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s10495-024-01991-0
Cancer Res. 2024 Jul 29.

Hyperactive DCs redirect aged anti-tumor immunity.

Alex C Y Chen, Debattama R Sen.

Aging is one of the biggest risk factors for cancer development. Over 85% of all cancers occur in individuals aged over 55 years, often accompanied by age-associated immune defects. Previous studies on the tumor microenvironment (TME) during aging have identified several factors, such as the roles of fibroblasts, immunosuppression, and metastasis. However, the aging-associated defects in anti-tumor immunity, particularly regarding T cells, remain underexplored. Recent findings by Zhivaki and colleagues suggest that age-related immune defects affecting anti-tumor responses involve reduced levels of CD8+ T cells and compromised dendritic cell (DC) functions such as antigen presentation and migration. Their study demonstrates that a hyperactive DC vaccine can restore DC functions in older mice. Furthermore, these hyperactive DCs, characterized by increased IL-1β production and better migratory capability to the lymph node, promote the development of cytolytic CD4+ T cells exhibiting Th1-like phenotypes. This research reveals mechanisms underlying the response to hyperactive DC vaccines in older mice and highlights the critical role of cytolytic CD4+ T cells as substitutes for CD8+ T cells in driving anti-tumor immunity and achieving long-term tumor control in older mice.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2650
Front Immunol. 2024 ;15 1428118

Targeting the tumor microenvironment to improve clinical outcomes in triple negative breast cancer patients and bridge the current disparity gap.

Malak Alharbi, Arya Mariam Roy, Jayasree Krishnan, Pawel Kalinski, Song Yao, Shipra Gandhi.

  Triple negative breast cancer (TNBC) is a heterogenous disease that disproportionately affects Black women. TNBC outcomes among Black women are dismal secondary to multiple factors, such as poor healthcare accessibility resulting in delays in diagnosis, and aggressive disease biology in addition to a pro-tumor immune microenvironment (TME). Black women with breast cancer exhibit elevated levels of serum pro-inflammatory cytokines, and a pro-tumorigenic TME with higher immunosuppressive regulatory T cells (Tregs), M2 macrophages and exhausted CD8+ T cells. We have shown that the combined use of toll-like receptor 3 (TLR3) ligands with interferon-α (chemokine modulation: CKM) is able to enrich the tumor with CD8+ T cells, while not increasing immunosuppressive cells. Recent clinical trials have revealed the efficacy of immune checkpoint inhibitors (ICI) in rejuvenizing exhausted CD8+ T cells. We hypothesize that strategies to modulate the TME by enriching chemokines that attract CD8+T cells followed by reversal of CD8+ T cell exhaustion (ICI), when added to standard treatment, could potentially improve clinical outcomes, and mitigate the racial disparities in TNBC outcomes between Black and White Women.

Keywords:  TLR3 agonist; exhausted CD8 + T cells; racial disparities; triple negative breast cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1428118
Biomed Pharmacother. 2024 Jul 27. pii: S0753-3322(24)01095-3. [Epub ahead of print]178 117211

How neutrophils shape the immune response of triple-negative breast cancer: Novel therapeutic strategies targeting neutrophil extracellular traps.

Bing Liang, Ye Yuan, Qianheng Jiang, Tao Ma, Xiaodan Liu, Yan Li.

  Triple-negative breast cancer (TNBC) is labeled as an aggressive type of breast cancer and still has limited therapeutic targets despite the advanced development of cancer therapy. Neutrophils, representing the conventional inflammatory response, significantly influence the malignant phenotype of tumors, supported by abundant evidence. As a vital function of neutrophils, NETs are the extracellular fibrous networks including the depolymerized chromatin DNA frames with several antimicrobial proteins. They are produced by activated neutrophils and are involved in host defence or immunological reactions. This review focuses more on the interactions between neutrophils and TNBC, focusing on how neutrophils modulate the immune response within the tumor milieu. Specifically, we delve into the role of NETs, which are involved in promoting tumor growth and metastasis, inhibiting anti-tumor immunity, and promoting tumor-associated thrombosis. Furthermore, we discuss recent advancements in therapeutic strategies aimed at targeting NETs to enhance the efficacy of TNBC treatment. The advances in the knowledge of the dynamics between neutrophils and TNBC may lead to the opportunity to devise new immunotherapeutic strategies targeted to fight this hostile type of breast cancer.

Keywords:  Immune regulation; Neutrophil; Neutrophil extracellular traps; Targeted therapy; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.biopha.2024.117211
Oncoimmunology. 2024 ;13(1): 2381803

S100A10 promotes cancer metastasis via recruitment of MDSCs within the lungs.

Juan Li, Can Zhou, Xiaoqian Gao, Tan Tan, Miao Zhang, Yazhao Li, He Chen, Ruiqi Wang, Bo Wang, Jie Liu, Peijun Liu.

  Tumor-derived exosomes bind to organ resident cells, activating S100 molecules during the remodeling of the local immune microenvironment. However, little is known regarding how organ resident cell S100A10 mediates cancer metastatic progression. Here, we provided evidence that S100A10 plays an important role in regulating the lung immune microenvironment and cancer metastasis. S100A10-deficient mice reduced cancer metastasis in the lung. Furthermore, the activation of S100A10 within lung fibroblasts via tumor-derived exosomes increased the expression of CXCL1 and CXCL8 chemokines, accompanied by the myeloid-derived suppressor cells (MDSCs) recruitment. S100A10 inhibitors such as 1-Substituted-4-Aroyl-3-hydroxy-5-Phenyl-1 H-5-pyrrol-2(5 H)-ones inhibit lung metastasis in vivo. Our findings highlight the crucial role of S100A10 in driving MDSC recruitment in order to remodel the lung immune microenvironment and provide potential therapeutic targets to block cancer metastasis to the lung.

Keywords:  Cancer metastasis; S100A10; lung fibroblasts; myeloid-derived suppressor cells

DOI:  https://doi.org/10.1080/2162402X.2024.2381803
Oncol Rev. 2024 ;18 1411736

Extracellular vesicles and cancer stem cells: a deadly duo in tumor progression.

Akram Tayanloo-Beik, Azin Eslami, Masoumeh Sarvari, Hasan Jalaeikhoo, Mohsen Rajaeinejad, Mohsen Nikandish, Ali Faridfar, Mostafa Rezaei-Tavirani, Ahmad Rezazadeh Mafi, Bagher Larijani, Babak Arjmand.

  The global incidence of cancer is increasing, with estimates suggesting that there will be 26 million new cases and 17 million deaths per year by 2030. Cancer stem cells (CSCs) and extracellular vesicles (EVs) are key to the resistance and advancement of cancer. They play a crucial role in tumor dynamics and resistance to therapy. CSCs, initially discovered in acute myeloid leukemia, are well-known for their involvement in tumor initiation, progression, and relapse, mostly because of their distinct characteristics, such as resistance to drugs and the ability to self-renew. EVs, which include exosomes, microvesicles, and apoptotic bodies, play a vital role in facilitating communication between cells within the tumor microenvironment (TME). They have a significant impact on cellular behaviors and contribute to genetic and epigenetic changes. This paper analyzes the mutually beneficial association between CSCs and EVs, emphasizing their role in promoting tumor spread and developing resistance mechanisms. This review aims to investigate the interaction between these entities in order to discover new approaches for attacking the complex machinery of cancer cells. It highlights the significance of CSCs and EVs as crucial targets in the advancement of novel cancer treatments, which helps stimulate additional research, promote progress in ideas for cancer treatment, and provide renewed optimism in the effort to reduce the burden of cancer.

Keywords:  cancer stem cells; drug resistance; extracellular vesicles; precision medicine; tumor microenvironment

DOI:  https://doi.org/10.3389/or.2024.1411736
Front Pharmacol. 2024 ;15 1426033

Pericytes: jack-of-all-trades in cancer-related inflammation.

Marianna Moro, Federica Carolina Balestrero, Ambra A Grolla.

  Pericytes, recognized as mural cells, have long been described as components involved in blood vessel formation, playing a mere supporting role for endothelial cells (ECs). Emerging evidence strongly suggests their multifaceted roles in tissues and organs. Indeed, pericytes exhibit a remarkable ability to anticipate endothelial cell behavior and adapt their functions based on the specific cells they interact with. Pericytes can be activated by pro-inflammatory stimuli and crosstalk with immune cells, actively participating in their transmigration into blood vessels. Moreover, they can influence the immune response, often sustaining an immunosuppressive phenotype in most of the cancer types studied. In this review, we concentrate on the intricate crosstalk between pericytes and immune cells in cancer, highlighting the primary evidence regarding pericyte involvement in primary tumor mass dynamics, their contributions to tumor reprogramming for invasion and migration of malignant cells, and their role in the formation of pre-metastatic niches. Finally, we explored recent and emerging pharmacological approaches aimed at vascular normalization, including novel strategies to enhance the efficacy of immunotherapy through combined use with anti-angiogenic drugs.

Keywords:  cancer-related inflammation; immune evasion; metastasis; pericytes; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2024.1426033
Cancer Sci. 2024 Jul 31.

Tumor-derived mitochondrial formyl peptides suppress tumor immunity through modification of the tumor microenvironment.

Kayoko Waki, Miyako Ozawa, Keisuke Ohta, Nobukazu Komatsu, Akira Yamada.

  Mitochondrial N-formylpeptides are released from damaged or dead cells to the extracellular spaces and cause inflammatory responses. The role of mitochondrial N-formylpeptides in aseptic systemic inflammatory response syndromes induced by trauma or cardiac surgery has been well investigated. However, there are no reports regarding the role of mitochondrial N-formylpeptides in cancer. In this study, we investigated the role of tumor cell-derived mitochondrial N-formylpeptides in anti-tumor immunity using knockout murine tumor cells of mitochondrial methionyl-tRNA formyltransferase (MTFMT), which catalyze N-formylation of mitochondrial DNA-encoded proteins. There was no apparent difference among the wild-type and MTFMT-knockout clones of E.G7-OVA cells with respect to morphology, mitochondrial dynamics, glycolysis and oxidative phosphorylation, oxygen consumption rate, or in vitro cell growth. In contrast, in vivo tumor growth of MTFMT-knockout cells was slower than that of wild-type cells. A reduced number of myeloid-derived suppressor cells and an increase of cytotoxic T-lymphocytes in the tumor tissues were observed in the MTFMT-knockout tumors. These results suggested that tumor cell-derived mitochondrial N-formylpeptides had a negative role in the host anti-tumor immunity through modification of the tumor microenvironment.

Keywords:  DAMPs; alarmin; mitochondrial formyl peptide; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.16266
bioRxiv. 2024 Jul 19. pii: 2024.07.18.604156. [Epub ahead of print]

Systematic Analysis of Human Colorectal Cancer scRNA-seq Revealed Limited Pro-tumoral IL-17 Production Potential in Gamma Delta T Cells.

Ran Ran, Martin Trapecar, Douglas K Brubaker.

Gamma delta (γδ) T cells play a crucial role in anti-tumor immunity due to their cytotoxic properties. However, the role and extent of γδ T cells in production of pro-tumorigenic interleukin- 17 (IL-17) within the tumor microenvironment (TME) of colorectal cancer (CRC) remains controversial. In this study, we re-analyzed nine published human CRC whole-tissue single-cell RNA sequencing (scRNA-seq) datasets, identifying 18,483 γδ T cells out of 951,785 total cells, in the neoplastic or adjacent normal tissue of 165 human CRC patients. Our results confirm that tumor-infiltrating γδ T cells exhibit high cytotoxicity-related transcription in both tumor and adjacent normal tissues, but critically, none of the γδ T cell clusters showed IL-17 production potential. We also identified various γδ T cell subsets, including Teff, TRM, Tpex, and Tex, and noted an increased expression of cytotoxic molecules in tumor-infiltrating γδ T cells compared to their normal area counterparts. Our work demonstrates that γδ T cells in CRC primarily function as cytotoxic effector cells rather than IL-17 producers, mitigating the concerns about their potential pro-tumorigenic roles in CRC, highlighting the importance of accurately characterizing these cells for cancer immunotherapy research and the unneglectable cross-species discrepancy between the mouse and human immune system in the study of cancer immunology.

DOI: https://doi.org/10.1101/2024.07.18.604156
J Exp Clin Cancer Res. 2024 Aug 02. 43(1): 214

Tumor-derived GLI1 promotes remodeling of the immune tumor microenvironment in melanoma.

Alessandro Giammona, Chiara De Vellis, Enrica Crivaro, Luisa Maresca, Roberta Amoriello, Federica Ricci, Giulia Anichini, Silvia Pietrobono, David R Pease, Martin E Fernandez-Zapico, Clara Ballerini, Barbara Stecca.

   BACKGROUND: Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored.
METHODS: The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays.
RESULTS: Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8.
CONCLUSION: Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1.

Keywords:  CX3CL1; Dendritic cells; GLI1; Immune escape; Melanoma; Myeloid-derived suppressor cells

DOI:  https://doi.org/10.1186/s13046-024-03138-0
Front Mol Med. 2023 ;3 1239013

Editorial: CAR T-cells: novel therapeutic approaches in the new era of cancer immunotherapy.

Alice Turdo, Costanza Maria Cristiani, Niels Schaft.



Keywords:  CAR T-cell; cancer; immunotherapy; side effects; tumor microenvironment

DOI:  https://doi.org/10.3389/fmmed.2023.1239013
bioRxiv. 2024 Jul 16. pii: 2024.07.11.603114. [Epub ahead of print]

Localized in vivo gene editing of murine cancer-associated fibroblasts.

Nicholas F Kuhn, Itzia Zaleta-Linares, William A Nyberg, Justin Eyquem, Matthew F Krummel.

Discovering the role of fibroblasts residing in the tumor microenvironment (TME) requires controlled, localized perturbations because fibroblasts play critical roles in regulating immunity and tumor biology at multiple sites. Systemic perturbations can lead to unintended, confounding secondary effects, and methods to locally genetically engineer fibroblasts are lacking. To specifically investigate murine stromal cell perturbations restricted to the TME, we developed an adeno-associated virus (AAV)-based method to target any gene-of-interest in fibroblasts at high efficiency (>80%). As proof of concept, we generated single (sKO) and double gene KOs (dKO) of Osmr , Tgfbr2 , and Il1r1 in cancer-associated fibroblasts (CAFs) and investigated how their cell states and those of other cells of the TME subsequently change in mouse models of melanoma and pancreatic ductal adenocarcinoma (PDAC). Furthermore, we developed an in vivo knockin-knockout (KIKO) strategy to achieve long-term tracking of CAFs with target gene KO via knocked-in reporter gene expression. This validated in vivo gene editing toolbox is fast, affordable, and modular, and thus holds great potential for further exploration of gene function in stromal cells residing in tumors and beyond.

DOI: https://doi.org/10.1101/2024.07.11.603114
Front Oncol. 2024 ;14 1420920

Immune checkpoint inhibitors targeting PD-1/PD-L1 in the treatment of human lymphomas.

Domenico Ribatti, Gerardo Cazzato, Roberto Tamma, Tiziana Annese, Giuseppe Ingravallo, Giorgina Specchia.

  Non-Hodgkin lymphomas (NHLs) encompass a diverse group of malignancies arising from B cells, T cells, and natural killer (NK) cells at various stages of differentiation. Conversely, classical Hodgkin lymphomas (cHLs) primarily feature Reed-Sternberg cells (RSCs) amid a background of reactive immune cells. Immunomodulatory pathways, notably the PD-1/PD-L1 axis, play pivotal roles in tumor immune evasion across both NHLs and cHLs. Elevated expression of PD-1 and PD-L1 is observed in a spectrum of lymphomas, influencing prognosis and treatment response. Therapeutically, immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have revolutionized lymphoma management, particularly in relapsed/refractory cases. Nivolumab and pembrolizumab, among others, have demonstrated efficacy in various B-cell lymphomas, with promising outcomes in cHL. Combination strategies incorporating ICIs with conventional chemotherapy or targeted agents show enhanced efficacy and are being explored extensively. In this review we discuss the most important features of the tumor microenvironment of NHLs and cHLs, address the therapeutic approaches with ICIs and try to outline future perspectives.

Keywords:  Hodgkin lymphoma; PD-1/PD-L1; immune checkpoint inhibitors; non-Hodgkin lymphoma; therapy

DOI:  https://doi.org/10.3389/fonc.2024.1420920
Front Cell Dev Biol. 2024 ;12 1412337

Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression.

Haoran Chen, Suping Fang, Xudong Zhu, Hao Liu.

  The functional heterogeneity and ecological niche of prostate cancer stem cells (PCSCs), which are major drivers of prostate cancer development and treatment resistance, have attracted considerable research attention. Cancer-associated fibroblasts (CAFs), which are crucial components of the tumor microenvironment (TME), substantially affect PCSC stemness. Additionally, CAFs promote PCSC growth and survival by releasing signaling molecules and modifying the surrounding environment. Conversely, PCSCs may affect the characteristics and behavior of CAFs by producing various molecules. This crosstalk mechanism is potentially crucial for prostate cancer progression and the development of treatment resistance. Using organoids to model the TME enables an in-depth study of CAF-PCSC interactions, providing a valuable preclinical tool to accurately evaluate potential target genes and design novel treatment strategies for prostate cancer. The objective of this review is to discuss the current research on the multilevel and multitarget regulatory mechanisms underlying CAF-PCSC interactions and crosstalk, aiming to inform therapeutic approaches that address challenges in prostate cancer treatment.

Keywords:  cancer-associated fibroblast; crosstalk; organoid; prostate cancer; prostate cancer stem cell

DOI:  https://doi.org/10.3389/fcell.2024.1412337
Front Immunol. 2024 ;15 1427443

Trained immunity inducers in cancer immunotherapy.

Yongjun Sui, Jay A Berzofsky.

  While most of the cancer immunotherapy strategies engage adaptive immunity, especially tumor-associated T cells, the small fraction of responding patients and types of cancers amenable, and the possibility of severe adverse effects limit its usage. More effective and general interventions are urgently needed. Recently, a de facto innate immune memory, termed 'trained immunity', has become a new research focal point, and promises to be a powerful tool for achieving long-term therapeutic benefits against cancers. Trained immunity-inducing agents such as BCG and fungal glucan have been shown to be able to avert the suppressive tumor microenvironment (TME), enhance T cell responses, and eventually lead to tumor regression. Here, we review the current understating of trained immunity induction and highlight the critical roles of emergency granulopoiesis, interferon γ and tissue-specific induction. Preclinical and clinical studies that have exploited trained immunity inducers for cancer immunotherapy are summarized, and repurposed trained immunity inducers from other fields are proposed. We also outline the challenges and opportunities for trained immunity in future cancer immunotherapies. We envisage that more effective cancer vaccines will combine the induction of trained immunity with T cell therapies.

Keywords:  T cell responses; cancer immunotherapy; interferon γ; trained immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1427443