bims-flamet 2024-09-08 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–09–08
twenty-six papers selected by
Peio Azcoaga, Biodonostia HRI

Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment.
Multi-armored allogeneic MUC1 CAR T cells enhance efficacy and safety in triple-negative breast cancer.
Single-cell transcriptional atlas of tumor-associated macrophages in breast cancer.
Crucial role of dendritic cells in the generation of anti-tumor T-cell responses and immunogenic tumor microenvironment to suppress tumor development.
Cancer associated fibroblasts and metabolic reprogramming: unraveling the intricate crosstalk in tumor evolution.
SLAM family-mediated crosstalk between tumor and immune cells in the tumor microenvironment: a promising biomarker and a potential therapeutic target for immune checkpoint therapies.
Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions.
Analysis of neuroglia and immune cells in the tumor microenvironment of breast cancer brain metastasis.
Myeloid-derived suppressor cells in cancer: Current knowledge and future perspectives.
Research progress on the role of PTEN deletion or mutation in the immune microenvironment of glioblastoma.
Dissecting the roles of exosomal cancer-associated fibroblasts-derived non-coding RNAs in tumor progression: A complete guide.
NK/DC crosstalk-modulating antitumor activity via Sema3E/PlexinD1 axis for enhanced cancer immunotherapy.
Nanoreactors with Cascade Catalytic Activity Reprogram the Tumor Microenvironment for Enhanced Immunotherapy by Synchronously Regulating Treg and Macrophage Cells.
Mammary hydroxylated oestrogen activates the NLRP3 inflammasome in tumor-associated macrophages to promote breast cancer progression and metastasis.
Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment.
PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.
Tumor‑associated macrophages activated in the tumor environment of hepatocellular carcinoma: Characterization and treatment (Review).
Cellular senescence and SASP in tumor progression and therapeutic opportunities.
Dual Oxygen-Supply Immunosuppression-Inhibiting Nanomedicine to Avoid the Intratumoral Recruitment of Myeloid-Derived Suppressor Cells.
Effector Functions of Dendritic Cells in Cancer: Role of Cytotoxicity and Growth Inhibition.
Tumor Microenvironment: From Cervical Carcinogenesis to Therapeutic Advancements.
Recapitulating the Cancer-Immunity Cycle on a Chip.
Combined targeting of senescent cells and senescent macrophages: A new idea for integrated treatment of lung cancer.
Single-cell landscape of intratumoral heterogeneity and tumor microenvironment remolding in pre-nodal metastases of breast cancer.
Lessons from Post-Immunotherapy Tumor Tissues in Clinical Trials: How Can We Fuel the Tumor Microenvironment in Gliomas?
New perspectives on chemokines in hepatocellular carcinoma therapy: a critical pathway for natural products regulation of the tumor microenvironment.

Biomark Res. 2024 Sep 03. 12(1): 96

Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment.

Haixia Zhang, Shizhen Li, Dan Wang, Siyang Liu, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Minghua Yang, Pan Chen.

  Tumor cells possess complex immune evasion mechanisms to evade immune system attacks, primarily through metabolic reprogramming, which significantly alters the tumor microenvironment (TME) to modulate immune cell functions. When a tumor is sufficiently immunogenic, it can activate cytotoxic T-cells to target and destroy it. However, tumors adapt by manipulating their metabolic pathways, particularly glucose, amino acid, and lipid metabolism, to create an immunosuppressive TME that promotes immune escape. These metabolic alterations impact the function and differentiation of non-tumor cells within the TME, such as inhibiting effector T-cell activity while expanding regulatory T-cells and myeloid-derived suppressor cells. Additionally, these changes lead to an imbalance in cytokine and chemokine secretion, further enhancing the immunosuppressive landscape. Emerging research is increasingly focusing on the regulatory roles of non-tumor cells within the TME, evaluating how their reprogrammed glucose, amino acid, and lipid metabolism influence their functional changes and ultimately aid in tumor immune evasion. Despite our incomplete understanding of the intricate metabolic interactions between tumor and non-tumor cells, the connection between these elements presents significant challenges for cancer immunotherapy. This review highlights the impact of altered glucose, amino acid, and lipid metabolism in the TME on the metabolism and function of non-tumor cells, providing new insights that could facilitate the development of novel cancer immunotherapies.

Keywords:  Immune evasion; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40364-024-00646-1
Sci Adv. 2024 Aug 30. 10(35): eadn9857

Multi-armored allogeneic MUC1 CAR T cells enhance efficacy and safety in triple-negative breast cancer.

Piril Erler, Tomasz Kurcon, Hana Cho, Jordan Skinner, Chantel Dixon, Steven Grudman, Sandra Rozlan, Emilie Dessez, Ben Mumford, Sumin Jo, Alex Boyne, Alexandre Juillerat, Philippe Duchateau, Laurent Poirot, Beatriz Aranda-Orgilles.

Solid tumors, such as triple-negative breast cancer (TNBC), are biologically complex due to cellular heterogeneity, lack of tumor-specific antigens, and an immunosuppressive tumor microenvironment (TME). These challenges restrain chimeric antigen receptor (CAR) T cell efficacy, underlining the importance of armoring. In solid cancers, a localized tumor mass allows alternative administration routes, such as intratumoral delivery with the potential to improve efficacy and safety but may compromise metastatic-site treatment. Using a multi-layered CAR T cell engineering strategy that allowed a synergy between attributes, we show enhanced cytotoxic activity of MUC1 CAR T cells armored with PD1KO, tumor-specific interleukin-12 release, and TGFBR2KO attributes catered towards the TNBC TME. Intratumoral treatment effectively reduced distant tumors, suggesting retention of antigen-recognition benefits at metastatic sites. Overall, we provide preclinical evidence of armored non-alloreactive MUC1 CAR T cells greatly reducing high TNBC tumor burden in a TGFB1- and PD-L1-rich TME both at local and distant sites while preserving safety.

DOI: https://doi.org/10.1126/sciadv.adn9857
Breast Cancer Res. 2024 Sep 04. 26(1): 129

Single-cell transcriptional atlas of tumor-associated macrophages in breast cancer.

Yupeng Zhang, Fan Zhong, Lei Liu.

   BACKGROUND: The internal heterogeneity of breast cancer, notably the tumor microenvironment (TME) consisting of malignant and non-malignant cells, has been extensively explored in recent years. The cells in this complex cellular ecosystem activate or suppress tumor immunity through phenotypic changes, secretion of metabolites and cell-cell communication networks. Macrophages, as the most abundant immune cells within the TME, are recruited by malignant cells and undergo phenotypic remodeling. Tumor-associated macrophages (TAMs) exhibit a variety of subtypes and functions, playing significant roles in impacting tumor immunity. However, their precise subtype delineation and specific function remain inadequately defined.
METHODS: The publicly available single-cell transcriptomes of 49,141 cells from eight breast cancer patients with different molecular subtypes and stages were incorporated into our study. Unsupervised clustering and manual cell annotation were employed to accurately classify TAM subtypes. We then conducted functional analysis and constructed a developmental trajectory for TAM subtypes. Subsequently, the roles of TAM subtypes in cell-cell communication networks within the TME were explored using endothelial cells (ECs) and T cells as key nodes. Finally, analyses were repeated in another independent publish scRNA datasets to validate our findings for TAM characterization.
RESULTS: TAMs are accurately classified into 7 subtypes, displaying anti-tumor or pro-tumor roles. For the first time, we identified a new TAM subtype capable of proliferation and expansion in breast cancer-TUBA1B+ TAMs playing a crucial role in TAMs diversity and tumor progression. The developmental trajectory illustrates how TAMs are remodeled within the TME and undergo phenotypic and functional changes, with TUBA1B+ TAMs at the initial point. Notably, the predominant TAM subtypes varied across different molecular subtypes and stages of breast cancer. Additionally, our research on cell-cell communication networks shows that TAMs exert effects by directly modulating intrinsic immunity, indirectly regulating adaptive immunity through T cells, as well as influencing tumor angiogenesis and lymphangiogenesis through ECs.
CONCLUSIONS: Our study establishes a precise single-cell atlas of breast cancer TAMs, shedding light on their multifaceted roles in tumor biology and providing resources for targeting TAMs in breast cancer immunotherapy.

Keywords:  Cell-cell communication; Cellular atlas; Single-cell transcriptome; TAMs; Tumor immunity

DOI:  https://doi.org/10.1186/s13058-024-01887-6
Front Immunol. 2024 ;15 1200461

Crucial role of dendritic cells in the generation of anti-tumor T-cell responses and immunogenic tumor microenvironment to suppress tumor development.

Moe Tominaga, Tomofumi Uto, Tomohiro Fukaya, Shuya Mitoma, Dieter Riethmacher, Kunihiko Umekita, Yoshihiro Yamashita, Katsuaki Sato.

  Dendritic cells (DCs) are known as unique professional antigen (Ag)-presenting cells (APCs) to prime naïve T cells for the initiation of adaptive immunity. While DCs are believed to play a pivotal role in generating anti-tumor T-cell responses, the importance of DCs in the protection from the progression of tumors remains elusive. Here, we show how the constitutive deficiency of CD11chi DCs influences the progression of tumors with the use of binary transgenic mice with constitutive loss of CD11chi DCs. Constitutive loss of CD11chi DCs not only enhances the progression of tumors but also reduces the responses of Ag-specific T cells. Furthermore, the congenital deficiency of CD11chi DCs generates the immunosuppressive tumor microenvironment (TME) that correlates with the marked accumulation of myeloid-derived suppressor cells (MDSCs) and the prominent productions of immunosuppressive mediators. Thus, our findings suggest that CD11chi DCs are crucial for generating anti-tumor T-cell responses and immunogenic TME to suppress the development of tumors.

Keywords:  anti-tumor T-cell responses; dendritic cells; immunosuppressive mediators; myeloid-derived suppressor cells; tumor development; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1200461
J Hematol Oncol. 2024 Sep 02. 17(1): 80

Cancer associated fibroblasts and metabolic reprogramming: unraveling the intricate crosstalk in tumor evolution.

Fusheng Zhang, Yongsu Ma, Dongqi Li, Jianlei Wei, Kai Chen, Enkui Zhang, Guangnian Liu, Xiangyu Chu, Xinxin Liu, Weikang Liu, Xiaodong Tian, Yinmo Yang.

  Metabolic reprogramming provides tumors with an energy source and biofuel to support their survival in the malignant microenvironment. Extensive research into the intrinsic oncogenic mechanisms of the tumor microenvironment (TME) has established that cancer-associated fibroblast (CAFs) and metabolic reprogramming regulates tumor progression through numerous biological activities, including tumor immunosuppression, chronic inflammation, and ecological niche remodeling. Specifically, immunosuppressive TME formation is promoted and mediators released via CAFs and multiple immune cells that collectively support chronic inflammation, thereby inducing pre-metastatic ecological niche formation, and ultimately driving a vicious cycle of tumor proliferation and metastasis. This review comprehensively explores the process of CAFs and metabolic regulation of the dynamic evolution of tumor-adapted TME, with particular focus on the mechanisms by which CAFs promote the formation of an immunosuppressive microenvironment and support metastasis. Existing findings confirm that multiple components of the TME act cooperatively to accelerate the progression of tumor events. The potential applications and challenges of targeted therapies based on CAFs in the clinical setting are further discussed in the context of advancing research related to CAFs.

Keywords:  Cancer-associated fibroblasts; Immune suppression; Inflammatory microenvironment; Metabolic reprogramming; Tumor metastasis; Tumor therapy

DOI:  https://doi.org/10.1186/s13045-024-01600-2
Clin Transl Oncol. 2024 Aug 30.

SLAM family-mediated crosstalk between tumor and immune cells in the tumor microenvironment: a promising biomarker and a potential therapeutic target for immune checkpoint therapies.

Louis Boafo Kwantwi.

  Immune cells infiltrating the tumor microenvironment are physiologically important in controlling cancers. However, emerging studies have shown that cancer cells can evade immune surveillance and establish a balance in which these immune cells support tumor progression and therapeutic resistance. The signaling lymphocytic activation molecule family members have been recognized as mediators of tumor microenvironment interactions, and a promising therapeutic target for cancer immunotherapy. This review is focused on the role of SLAM family in tumor and immune cell interactions and discusses how such crosstalk affects tumor behavior. This will shed insight into the next step toward improving cancer immunotherapy.

Keywords:  Immune cells; Immune checkpoints inhibitors; SLAM family receptors; SLAMF; Signaling lymphocytic activation molecule family; Tumor cells; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12094-024-03675-2
Pharmacol Res. 2024 Aug 30. pii: S1043-6618(24)00327-X. [Epub ahead of print]208 107382

Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions.

Veronica Marabitti, Elisabetta Vulpis, Francesca Nazio, Silvia Campello.

  It is now recognized that tumors are not merely masses of transformed cells but are intricately interconnected with healthy cells in the tumor microenvironment (TME), forming complex and heterogeneous structures. Recent studies discovered that cancer cells can steal mitochondria from healthy cells to empower themselves, while reducing the functions of their target organ. Mitochondrial transfer, i.e. the intercellular movement of mitochondria, is recently emerging as a novel process in cancer biology, contributing to tumor growth, metastasis, and resistance to therapy by shaping the metabolic landscape of the tumor microenvironment. This review highlights the influence of transferred mitochondria on cancer bioenergetics, redox balance and apoptotic resistance, which collectively foster aggressive cancer phenotype. Furthermore, the therapeutic implications of mitochondrial transfer are discussed, emphasizing the potential of targeting these pathways to overcome drug resistance and improve treatment efficacy.

Keywords:  Mitochondria transfer; cancer therapy; metabolic alterations; tumor microenvironment

DOI:  https://doi.org/10.1016/j.phrs.2024.107382
Cancer Biol Ther. 2024 Dec 31. 25(1): 2398285

Analysis of neuroglia and immune cells in the tumor microenvironment of breast cancer brain metastasis.

Haixin Mo, Xin Zhang, Liangliang Ren.

  Breast cancer stands as the most prevalent cancer diagnosed worldwide, often leading to brain metastasis, a challenging complication characterized by high mortality rates and a grim prognosis. Understanding the intricate mechanisms governing breast cancer brain metastasis (BCBM) remains an ongoing challenge. The unique microenvironment in the brain fosters an ideal setting for the colonization of breast cancer cells. The tumor microenvironment (TME) in brain metastases plays a pivotal role in the initiation and progression of BCBM, shaping the landscape for targeted therapeutic interventions. Current research primarily concentrates on unraveling the complexities of the TME in BCBM, with a particular emphasis on neuroglia and immune cells, such as microglia, monocyte-derived macrophages (MDMs), astrocytes and T cells. This comprehensive review delves deeply into these elements within the TME of BCBM, shedding light on their interplay, mechanisms, and potential as therapeutic targets to combat BCBM.

Keywords:  Breast cancer; brain metastasis; immune cells; neuroglia; tumor microenvironment

DOI:  https://doi.org/10.1080/15384047.2024.2398285
Int Immunopharmacol. 2024 Sep 04. pii: S1567-5769(24)01470-X. [Epub ahead of print]142(Pt A): 112949

Myeloid-derived suppressor cells in cancer: Current knowledge and future perspectives.

Sunanda Rajkumari, Jaspreet Singh, Usha Agrawal, Sandeep Agrawal.

  MDSCs (myeloid-derived suppressor cells) are crucial for immune system evasion in cancer. They accumulate in peripheral blood and tumor microenvironment, suppressing immune cells like T-cells, natural killer cells and dendritic cells. They promote tumor angiogenesis and metastasis by secreting cytokines and growth factors and contribute to a tumor-promoting environment. The accumulation of MDSCs in cancer patients has been linked to poor prognosis and resistance to various cancer therapies. Targeting MDSCs and their immunosuppressive mechanisms may improve treatment outcomes and enhance immune surveillance by developing drugs that inhibit MDSC function, by preventing their accumulation and by disrupting the tumor-promoting environment. This review presents a detailed overview of the MDSC research in cancer with regulation of their development and function. The relevance of MDSC as a prognostic and predictive biomarker in different types of cancers, along with recent advancements on the therapeutic approaches to target MDSCs are discussed in detail.

Keywords:  Cancer immunology; Cancer immunotherapy; Chemokines; Cytokines; Myeloid-derived suppressor cells (MDSC); Prognostic biomarkers

DOI:  https://doi.org/10.1016/j.intimp.2024.112949
Front Oncol. 2024 ;14 1409519

Research progress on the role of PTEN deletion or mutation in the immune microenvironment of glioblastoma.

Leiya Du, Qian Zhang, Yi Li, Ting Li, Qingshan Deng, Yuming Jia, Kaijian Lei, Daohong Kan, Fang Xie, Shenglan Huang.

  Recent advances in immunotherapy represent a breakthrough in solid tumor treatment but the existing data indicate that immunotherapy is not effective in improving the survival time of patients with glioblastoma. The tumor microenvironment (TME) exerts a series of inhibitory effects on immune effector cells, which limits the clinical application of immunotherapy. Growing evidence shows that phosphate and tension homology deleted on chromosome ten (PTEN) plays an essential role in TME immunosuppression of glioblastoma. Emerging evidence also indicates that targeting PTEN can improve the anti-tumor immunity in TME and enhance the immunotherapy effect, highlighting the potential of PTEN as a promising therapeutic target. This review summarizes the function and specific upstream and downstream targets of PTEN-associated immune cells in glioblastoma TME, providing potential drug targets and therapeutic options for glioblastoma.

Keywords:  PTEN; glioblastoma; immunity; immunosuppressive; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2024.1409519
Pathol Res Pract. 2024 Aug 30. pii: S0344-0338(24)00487-4. [Epub ahead of print]262 155576

Dissecting the roles of exosomal cancer-associated fibroblasts-derived non-coding RNAs in tumor progression: A complete guide.

Mahnaz Farahani, Mohammad H Ghazimoradi.

  Cancer-associated fibroblasts are the most important cellular component of the tumor microenvironment, controlling cancer progression and therapeutic response. These cells in the tumor microenvironment regulate tumor progression and development as oncogenic or tumor suppressor agents. However, the mechanisms by which CAFs communicate with cancer cells remain to investigate. Here, we review evidence that extracellular vesicles, particularly exosomes, serve as vehicles for the intercellular transfer of bioactive cargos, notably microRNAs and long non-coding RNAs, from CAFs to cancer cells. We try to highlight molecular pathways of non-coding RNAs and the interaction among these molecules. Together, these findings elucidate a critical exosome-based communication axis by which CAFs create mostly a supportive pro-tumorigenic microenvironment and highlight therapeutic opportunities for disrupting this intercellular crosstalk.

Keywords:  CAF; Cancer; Cancer-associated fibroblast; Exosome; LncRNA; MiRNA; NcRNA

DOI:  https://doi.org/10.1016/j.prp.2024.155576
Immunol Res. 2024 Sep 05.

NK/DC crosstalk-modulating antitumor activity via Sema3E/PlexinD1 axis for enhanced cancer immunotherapy.

Awais Ali, Abdulaziz Alamri, Azraida Hajar.

  The complex relationship between natural killer (NK) cells and dendritic cells (DCs) within the tumor microenvironment significantly impacts the success of cancer immunotherapy. Recent advancements in cancer treatment have sought to bolster innate and adaptive immune responses through diverse modalities, aiming to tilt the immune equilibrium toward tumor elimination. Optimal antitumor immunity entails a multifaceted interplay involving NK cells, T cells and DCs, orchestrating immune effector functions. Although DC-based vaccines and NK cells' cytotoxic capabilities hold substantial therapeutic potential, their interaction is frequently hindered by immunosuppressive elements such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells. Chemokines and cytokines, such as CXCL12, CCL2, interferons, and interleukins, play crucial roles in modulating NK/DC interactions and enhancing immune responses. This review elucidates the mechanisms underlying NK/DC interaction, emphasizing their pivotal roles in augmenting antitumor immune responses and the impediments posed by tumor-induced immunosuppression. Furthermore, it explores the therapeutic prospects of restoring NK/DC crosstalk, highlighting the significance of molecules like Sema3E/PlexinD1 in this context, offering potential avenues for enhancing the effectiveness of current immunotherapeutic strategies and advancing cancer treatment paradigms. Harnessing the dynamic interplay between NK and DC cells, including the modulation of Sema3E/PlexinD1 signaling, holds promise for developing more potent therapies that harness the immune system's full potential in combating cancer.

Keywords:  Antitumor immunity; Cancer immunotherapy; Cytokine administration; Monoclonal antibodies; NK and DCs cells; Sema3E/PlexinD1

DOI:  https://doi.org/10.1007/s12026-024-09536-y
ACS Appl Mater Interfaces. 2024 Sep 06.

Nanoreactors with Cascade Catalytic Activity Reprogram the Tumor Microenvironment for Enhanced Immunotherapy by Synchronously Regulating Treg and Macrophage Cells.

Yuhan Fu, Yuanyuan Zhang, Yujie Zhang, Runqing Li, Mei Yang, Ting Bai, Xiaoliang Zheng, Dongsheng Huang, Mingzhen Zhang, Kangsheng Tu, Qiuran Xu, Xin Liu.

  Immunotherapy has been extensively utilized and studied as a prominent therapeutic strategy for tumors. However, the presence of a hypoxic immunosuppressive tumor microenvironment significantly reduces the efficacy of the treatment, thus impeding its application. In addition, the hypoxic microenvironment can also lead to the enrichment of immunosuppressive cells and reduce the effectiveness of tumor immunotherapy; nanoparticles with biocatalytic activity have the ability to relieve hypoxia in tumor tissues and deliver drugs to target cells and have been widely concerned and applied in the field of tumor therapy. The present study involved the development of a dual nanodelivery system that effectively targets the immune system to modify the tumor microenvironment (TME). The nanodelivery system was developed by incorporating R848 and Imatinib (IMT) into Pt nanozyme loaded hollow polydopamine (P@HP) nanocarriers. Subsequently, their surface was modified with specifically targeted peptides that bind to M2-like macrophages and regulatory T (Treg) cells, thereby facilitating the precise targeting of these cells. When introduced into the tumor model, the nanocarriers were able to selectively target immune cells in tumor tissue, causing M2-type macrophages to change into the M1 phenotype and reducing Treg activation within the tumor microenvironment. In addition, the carriers demonstrated exceptional biocatalytic activity, effectively converting H2O2 into oxygen and water at the tumor site while the drug was active, thereby alleviating the hypoxic inhibitory conditions present in the tumor microenvironment. Additionally, this further enhanced the infiltration of M1-type macrophages and cytotoxic T lymphocytes. Moreover, when used in conjunction with immune checkpoint therapy, the proposed approach demonstrated enhanced antitumor immunotherapeutic effects. The bimodal targeted immunotherapeutic strategy developed in the present study overcomes the drawbacks of traditional immunotherapy approaches while offering novel avenues for the treatment of cancer.

Keywords:  Cancer immunotherapy; Nanodelivery system; Nanozymes; Tumor-associated Treg cells; Tumor-associated macrophages

DOI:  https://doi.org/10.1021/acsami.4c09830
Int Immunopharmacol. 2024 Sep 02. pii: S1567-5769(24)01555-8. [Epub ahead of print]142(Pt A): 113034

Mammary hydroxylated oestrogen activates the NLRP3 inflammasome in tumor-associated macrophages to promote breast cancer progression and metastasis.

Han Zhao, Jiahao Xu, Ya'nan Zhong, Shiqing He, Zhixiang Hao, Bei Zhang, Zhao Liu, Xueyan Zhou.

  Breast cancer remains one of the primary causes of cancer-related death. An imbalance of oestrogen homeostasis and an inflammatory tumor microenvironment (TME) are vital risk factors for the progression and metastasis of breast cancer. Here, we showed that oestrogen homeostasis was disrupted both in breast cancer patients and in a transgenic MMTV-PyMT mouse model of breast cancer, and significant levels of hydroxylated oestrogen accumulated in the mammary tissues of these patients and mice. We also observed that tumor-associated macrophages (TAMs) were the main population of immune cells present in the breast TME. TAM-dependent tumor metastasis could be triggered by hydroxylated oestrogen via NLRP3 inflammasome activation and IL-1β production. Mechanistically, TAM-derived inflammatory cytokines induced the expression of matrix metalloproteinases (MMPs) in breast tumor cells, leading to breast tumor invasion and metastasis. Conceptually, our study reveals a previously unknown role of hydroxylated oestrogen in the reprogramming of the TME via NLRP3 inflammasome activation in TAMs, which ultimately facilitates breast cancer cells proliferation, migration, and invasion.

Keywords:  Breast cancer; Metabolism; NLRP3 inflammasome; Oestrogen; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2024.113034
J Immunother Cancer. 2024 Aug 30. pii: e009160. [Epub ahead of print]12(8):

Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment.

Brenda C O'Connell, Charley Hubbard, Nora Zizlsperger, Donna Fitzgerald, Jeffrey L Kutok, Judith Varner, Robert Ilaria, Melody A Cobleigh, Dejan Juric, Kate H R Tkaczuk, Anthony Elias, Arielle Lee, Shaker Dakhil, Erika Hamilton, Hatem Soliman, Stephane Peluso.

   BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis particularly in the metastatic setting. Treatments with anti-programmed cell death protein-1/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICI) in combination with chemotherapies have demonstrated promising clinical benefit in metastatic TNBC (mTNBC) but there is still an unmet need, particularly for patients with PD-L1 negative tumors. Mechanisms of resistance to ICIs in mTNBC include the presence of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Eganelisib is a potent and selective, small molecule PI3K-γ inhibitor that was shown in preclinical studies to reshape the TME by reducing myeloid cell recruitment to tumors and reprogramming TAMs from an immune-suppressive to an immune-activating phenotype and enhancing activity of ICIs. These studies provided rationale for the clinical evaluation of eganelisib in combination with the anti-PD-L1 atezolizumab and nab-paclitaxel in firstline mTNBC in the phase 2 clinical trial MAcrophage Reprogramming in Immuno-Oncology-3 (MARIO-3, NCT03961698). We present here for the first time, in-depth translational analyses from the MARIO-3 study and supplemental data from eganelisib monotherapy Ph1/b study in solid tumors (MARIO-1, NCT02637531).
METHODS: Paired pre-treatment and post-treatment tumor biopsies were analyzed for immunophenotyping by multiplex immunofluorescence (n=11), spatial transcriptomics using GeoMx digital spatial profiling (n=12), and PD-L1 immunohistochemistry, (n=18). Peripheral blood samples were analyzed using flow cytometry and multiplex cytokine analysis.
RESULTS: Results from paired tumor biopsies from MARIO-3 revealed gene signatures of TAM reprogramming, immune activation and extracellular matrix (ECM) reorganization. Analysis of PD-L1 negative tumors revealed elevated ECM gene signatures at baseline that decreased after treatment. Gene signatures of immune activation were observed regardless of baseline PD-L1 status and occurred in patients having longer progression-free survival. Peripheral blood analyses revealed systemic immune activation.
CONCLUSIONS: This is the first report of translational analyses including paired tumor biopsies from a phase 2 clinical study of the first-in-class PI3K-γ inhibitor eganelisib in combination with atezolizumab and nab-paclitaxel in frontline mTNBC. These results support the mechanism of action of eganelisib as a TAM-reprogramming immunotherapy and support the rationale for combining eganelisib with ICI and chemotherapy in indications with TAM-driven resistance to ICI.

Keywords:  Breast Cancer; Immune Checkpoint Inhibitors; Immunotherapy; Macrophage; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-009160
Immunity. 2024 Aug 22. pii: S1074-7613(24)00376-5. [Epub ahead of print]

PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.

Yu Ping, Jiqi Shan, Haiming Qin, Feng Li, Jiao Qu, Ru Guo, Dong Han, Wei Jing, Yaqing Liu, Jinyan Liu, Zhangnan Liu, Jieyao Li, Dongli Yue, Feng Wang, Liping Wang, Bin Zhang, Bo Huang, Yi Zhang.

  The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1-/- CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1-/- CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy.

Keywords:  CD8(+) T cell; PD-1 signaling; PLPP1; anti-PD-1 therapy; antitumor immunity; ferroptosis; lipid peroxidation; phospholipid metabolism; tumor microenvironment; unsaturated fatty acid

DOI:  https://doi.org/10.1016/j.immuni.2024.08.003
Int J Oncol. 2024 Oct;pii: 100. [Epub ahead of print]65(4):

Tumor‑associated macrophages activated in the tumor environment of hepatocellular carcinoma: Characterization and treatment (Review).

Mingkai Yu, Haixia Yu, Hongmei Wang, Xiaoya Xu, Zhaoqing Sun, Wenshuai Chen, Miaomiao Yu, Chunhua Liu, Mingchun Jiang, Xiaowei Zhang.

  Hepatocellular carcinoma (HCC) tissue is rich in dendritic cells, T cells, B cells, macrophages, natural killer cells and cellular stroma. Together they form the tumor microenvironment (TME), which is also rich in numerous cytokines. Tumor‑associated macrophages (TAMs) are involved in the regulation of tumor development. TAMs in HCC receive stimuli in different directions, polarize in different directions and release different cytokines to regulate the development of HCC. TAMs are mostly divided into two cell phenotypes: M1 and M2. M1 TAMs secrete pro‑inflammatory mediators, and M2 TAMs secrete a variety of anti‑inflammatory and pro‑tumorigenic substances. The TAM polarization in HCC tumors is M2. Both direct and indirect methods for TAMs to regulate the development of HCC are discussed. TAMs indirectly support HCC development by promoting peripheral angiogenesis and regulating the immune microenvironment of the TME. In terms of the direct regulation between TAMs and HCC cells, the present review mainly focuses on the molecular mechanism. TAMs are involved in both the proliferation and apoptosis of HCC cells to regulate the quantitative changes of HCC, and stimulate the related invasive migratory ability and cell stemness of HCC cells. The present review aims to identify immunotherapeutic options based on the mechanisms of TAMs in the TME of HCC.

Keywords:  hepatocellular carcinoma; immunotherapy; tumor microenvironment; tumorigenesis; tumor‑associated macrophages

DOI:  https://doi.org/10.3892/ijo.2024.5688
Mol Cancer. 2024 Aug 31. 23(1): 181

Cellular senescence and SASP in tumor progression and therapeutic opportunities.

Zening Dong, Yahan Luo, Zhangchen Yuan, Yu Tian, Tianqiang Jin, Feng Xu.

  Cellular senescence (CS), a permanent and irreversible arrest of the cell cycle and proliferation leading to the degeneration of cellular structure and function, has been implicated in various key physiological and pathological processes, particularly in cancer. Initially, CS was recognized as a barrier to tumorigenesis, serving as an intrinsic defense mechanism to protect cells from malignant transformation. However, increasing evidence suggests that senescent cells can promote tumor progression to overt malignancy, primarily through a set of factors known as senescence-associated secretory phenotypes (SASPs), including chemokines, growth factors, cytokines, and stromal metalloproteinases. These factors significantly reshape the tumor microenvironment (TME), enabling tumors to evade immune destruction. Interestingly, some studies have also suggested that SASPs may impede tumor development by enhancing immunosurveillance. These opposing roles highlight the complexity and heterogeneity of CS and SASPs in diverse cancers. Consequently, there has been growing interest in pharmacological interventions targeting CS or SASPs in cancer therapy, such as senolytics and senomorphics, to either promote the clearance of senescent cells or mitigate the harmful effects of SASPs. In this review, we will interpret the concept of CS, delve into the role of SASPs in reshaping the TME, and summarize recent advances in anti-tumor strategies targeting CS or SASPs.

Keywords:  Cellular senescence; SASP; Therapy; Tumor; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-024-02096-7
Small. 2024 Sep 05. e2406860

Dual Oxygen-Supply Immunosuppression-Inhibiting Nanomedicine to Avoid the Intratumoral Recruitment of Myeloid-Derived Suppressor Cells.

Zhengyang Yang, Huaqin Zuo, Yuchen Hou, Shuqin Zhou, Ying Zhang, Wanren Yang, Jian He, Xiaofei Shen, Qing Peng.

  Myeloid-derived suppressor cells (MDSCs) are reported to be responsible for the negative prognosis of colorectal cancer (CRC) patients due to the mediated immunosuppressive tumor microenvironment (TME). The selective and chronic circumvention of tumor-infiltrated MDSCs has potential clinical significance for CRC treatment, which unluckily remains a technical challenge. Because tumor hypoxia makes a significant contribution to the recruitment of MDSCs in tumor sites, a dual oxygen-supplied immunosuppression-inhibiting nanomedicine (DOIN) is demonstrated for overcoming tumor hypoxia, which achieves selective and long-term inhibition of intratumoral recruitment of MDSCs. The DOIN is constructed by the encasement of perfluorooctyl bromide (PFOB) and 4-methylumbelliferone (4-MU) into a TME-responsive amphiphilic polymer. This nanoplatform directly carries oxygen to the tumor region and simultaneously loosens the condensed tumor extracellular matrix for the normalization of tumor vasculature, which selectively remodels the TME toward one adverse to the intratumoral recruitment of MDSCs. Importantly, this nanoplatform offers a long-acting alleviation of the hypoxic TME, chronically avoiding the comeback of tumor-infiltrated MDSCs. Consequently, the immunosuppressive TME is relieved, and T cells are successfully proliferated and activated into cytotoxic T lymphocytes, which boosts a systemic immune response and contributes to lasting inhibition of tumor growth with a prolonged survival span of xenograft.

Keywords:  colorectal cancer; enhanced immunoreactivity; hypoxic tumor microenvironment; myeloid‐derived suppressor cells; nanoplatform

DOI:  https://doi.org/10.1002/smll.202406860
Front Biosci (Landmark Ed). 2024 Aug 20. 29(8): 293

Effector Functions of Dendritic Cells in Cancer: Role of Cytotoxicity and Growth Inhibition.

Pratima Chaudhary, Prateek Srivastava, Partha Pratim Manna.

  The tumor microenvironment plays a critical role in modulating immune responses associated with tumorigenesis, tumor progression, and metastasis. Dendritic cells (DC) play a key role in preventing and progression of metastatic neoplasia by driving and restoring dysfunctional immune systems and obliterating immunosuppression, thus obstructing tumor evasion. In this review, we will discuss the functions of tumor-infiltrating DC in anti-tumor resistance, prevention of tumor recurrence, and immunosuppression. We will also describe DC metabolism, differentiation, and plasticity, which are essential for its function. Cancers like Lymphomas may be able to corrupt immune surveillance by reducing natural killer cell numbers. Thus, interactions between lymphoma and DC with reference to cytotoxicity may be an important event, likely to be mediated via activation with interferon-γ (IFN-γ) and Toll like receptors (TLR) ligands. Mechanisms of DC-mediated cytotoxicity and the role of apoptosis and death receptors, including the role played by nitric oxide, etc., are of immense significance. We will also look into the molecular mechanisms in the tumor microenvironment, reduced drug sensitivity, and tumor relapse, as well as methods for combating drug resistance and focusing on immunosuppressive tumor networks. We will address how DC mediated cytotoxicity in combination with drugs affects tumor growth and expansion in relation to checkpoint inhibitors and regulatory T cells. Innovative approaches for therapeutic modulation of this immunosuppressive adoptive DC immunotherapy will be highlighted, which is necessary for future personalized therapeutic applications.

Keywords:  anti-cancer drugs; cancer; combination therapy; cross-priming; cytotoxicity; dendritic cells; effector functions; immunosuppression; metastasis; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.31083/j.fbl2908293
Curr Pharm Biotechnol. 2024 Sep 04.

Tumor Microenvironment: From Cervical Carcinogenesis to Therapeutic Advancements.

Srishti Sharma, Meenakshi Verma, Indra Rautela, Fahad Khan, Pratibha Pandey.

  Cervical cancer has become a major worldwide health concern that demands attention to women's health and often needs more effective and specialized treatment options. Cervical cancer claims the lives of over 300,000 women globally, ranking as the fourth most prevalent cancer among women. The tumor microenvironment (TME) shapes a distinctive landscape for tumor survival, characterized by factors like immunosuppression, hypoxia, acidity, and nutrient scarcity. Comprising tumor cells, immune cells, mesenchymal cells, cancer-associated fibroblasts, and extracellular matrix, the TME reprograms key aspects of tumor development, uncontrolled proliferation, invasion, metastasis, and response to treatments. Recognizing the TME's pivotal role in tumor progression and treatment responsiveness, targeting the TME has emerged as a potential strategy in cancer therapy. This publication delves into recent TME research, offering a comprehensive overview of the specific functions of each TME component in cancer development and progression. Based on the reviewed literature, it appears that women with cervical cancer may benefit from more effective therapy, fewer side effects, and a higher quality of life in the future. By addressing pressing problems and unmet needs in the field, this review has the potential to significantly alter the course of cervical cancer treatment in the future. Furthermore, it outlines the primary therapeutic targets identified by researchers, which may prove valuable in treating tumors.

Keywords:  Cervical cancer; TME; drug designing; therapeutics.; tumor

DOI:  https://doi.org/10.2174/0113892010315757240821063137
Adv Healthc Mater. 2024 Sep 02. e2401927

Recapitulating the Cancer-Immunity Cycle on a Chip.

Yujin Lee, Jaehong Min, Solbin Kim, Wooju Park, Jihoon Ko, Noo Li Jeon.

  The cancer-immunity cycle is a fundamental framework for understanding how the immune system interacts with cancer cells, balancing T cell recognition and elimination of tumors while avoiding autoimmune reactions. Despite advancements in immunotherapy, there remains a critical need to dissect each phase of the cycle, particularly the interactions among the tumor, vasculature, and immune system within the tumor microenvironment (TME). Innovative platforms such as organ-on-a-chip, organoids, and bioprinting within microphysiological systems (MPS) are increasingly utilized to enhance the understanding of these interactions. These systems meticulously replicate crucial aspects of the TME and immune responses, providing robust platforms to study cancer progression, immune evasion, and therapeutic interventions with greater physiological relevance. This review explores the latest advancements in MPS technologies for modeling various stages of the cancer-immune cycle, critically evaluating their applications and limitations in advancing the understanding of cancer-immune dynamics and guiding the development of next-generation immunotherapeutic strategies.

Keywords:  Immune system; cancer‐immunity cycle; microphysiological systems; organ‐on‐a‐chip; tumor microenvironment

DOI:  https://doi.org/10.1002/adhm.202401927
Semin Cancer Biol. 2024 Aug 29. pii: S1044-579X(24)00070-1. [Epub ahead of print]106-107 43-57

Combined targeting of senescent cells and senescent macrophages: A new idea for integrated treatment of lung cancer.

Ming Gu, Yang Liu, Wenhui Zheng, Zuoqian Jing, Xiang Li, Wei Guo, Zimo Zhao, Xu Yang, Zhe Liu, Xinwang Zhu, Wei Gao.

  Lung cancer is one of the most common cancers worldwide and a leading cause of cancer-related deaths. Macrophages play a key role in the immune response and the tumour microenvironment. As an important member of the immune system, macrophages have multiple functions, including phagocytosis and clearance of pathogens, modulation of inflammatory responses, and participation in tissue repair and regeneration. In lung cancer, macrophages are considered to be the major cellular component of the tumor-associated inflammatory response and are closely associated with tumorigenesis, progression and metastasis. However, macrophages gradually undergo a senescence process with age and changes in pathological states. Macrophage senescence is an important change in the functional and metabolic state of macrophages and may have a significant impact on lung cancer development. In lung cancer, senescent macrophages interact with other cells in the tumor microenvironment (TME) by secreting senescence-associated secretory phenotype (SASP) factors, which can either promote the proliferation, invasion and metastasis of tumor cells or exert anti-tumor effects through reprogramming or clearance under specific conditions. Therefore, senescent macrophages are considered important potential targets for lung cancer therapy. In this paper, a systematic review of macrophages and their senescence process, and their role in tumors is presented. A variety of inhibitory strategies against senescent macrophages, including enhancing autophagy, inhibiting SASP, reducing DNA damage, and modulating metabolic pathways, were also explored. These strategies are expected to improve lung cancer treatment outcomes by restoring the anti-tumor function of macrophages.

Keywords:  Immune senescence; Macrophage; Narrative review; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2024.08.006
J Transl Med. 2024 Aug 29. 22(1): 804

Single-cell landscape of intratumoral heterogeneity and tumor microenvironment remolding in pre-nodal metastases of breast cancer.

Kaidong Liu, Huiming Han, Kai Xiong, Songmei Zhai, Xiuqi Yang, Xinmiao Yu, Bo Chen, Mingyue Liu, Qi Dong, Hongxue Meng, Yunyan Gu.

   BACKGROUND: The metastasis of cancer cells is influenced by both their intrinsic characteristics and the tumor microenvironment (TME). However, the molecular mechanisms underlying pre-nodal metastases of breast cancer remain unclear.
METHODS: We integrated a total of 216,963 cells from 54 samples across 6 single-cell datasets to profile the cellular landscape differences between primary tumors and pre-nodal metastases.
RESULTS: We revealed three distinct metastatic epithelial cell subtypes (Epi1, Epi2 and Epi3), which exhibited different metastatic mechanisms. Specifically, the marker gene KCNK15 of the Epi1 subtype exhibited increased gene expression along the cell differentiation trajectory and was specifically regulated by the transcription factor ASCL1. In the Epi3 subtype, we highlighted NR2F1 as a regulator targeting the marker gene MUCL1. Additionally, we found that the Epi2 and Epi3 subtypes shared some regulons, such as ZEB1 and NR2C1. Similarly, we identified specific subtypes of stromal and immune cells in the TME, and discovered that vascular cancer-associated fibroblasts might promote capillary formation through CXCL9+ macrophages in pre-nodal metastases. All three subtypes of metastatic epithelial cells were associated with poor prognosis.
CONCLUSIONS: In summary, this study dissects the intratumoral heterogeneity and remodeling of the TME in pre-nodal metastases of breast cancer, providing novel insights into the mechanisms underlying breast cancer metastasis.

Keywords:  Breast cancer; Pre-nodal metastasis; Single-cell analysis; Tumor microenvironment remodeling

DOI:  https://doi.org/10.1186/s12967-024-05625-6
Vaccines (Basel). 2024 Aug 01. pii: 862. [Epub ahead of print]12(8):

Lessons from Post-Immunotherapy Tumor Tissues in Clinical Trials: How Can We Fuel the Tumor Microenvironment in Gliomas?

Lan Hoc Phung, Takahide Nejo, Hideho Okada.

  Despite recent advancements in cancer immunotherapy, many patients with gliomas and glioblastomas have yet to experience substantial therapeutic benefits. Modulating the tumor microenvironment (TME) of gliomas, which is typically "cold", is crucial for improving treatment outcomes. Clinical tumor specimens obtained post-immunotherapy provide invaluable insights. However, access to such post-immunotherapy samples remains limited, even in clinical trials, as tumor tissues are often collected only at tumor relapse. Recent studies of neoadjuvant immunotherapy provided important insights by incorporating surgical resections of post-treatment tumors. Moreover, pre-surgical immunotherapies are increasingly integrated into clinical trial designs to evaluate treatment efficacy. These investigations reveal critical information, particularly regarding the delivery success of therapeutic agents, the expansion and persistence of immune products, and the cellular and molecular changes induced in the TME. In this review, we assess the findings on post-treatment tumor specimens obtained from recent immunotherapy clinical trials on gliomas, highlight the importance of these samples for understanding therapeutic impacts, and discuss proactive investigation approaches for future clinical trials.

Keywords:  clinical trials; glioblastoma; glioma; immunotherapy; neoadjuvant treatment; trial designs; tumor microenvironment

DOI:  https://doi.org/10.3390/vaccines12080862
Front Immunol. 2024 ;15 1456405

New perspectives on chemokines in hepatocellular carcinoma therapy: a critical pathway for natural products regulation of the tumor microenvironment.

Xie Ruishi, Xu Linyi, Bai Yunfan, Yu Wenbo, Zhang Xiaoying, Fang Xiaoxue, Zhu Difu, Lan Xintian, Zhu Ming, Luo Haoming.

  Hepatocellular carcinoma (HCC) is one of the most common primary neoplasms of the liver and one of the most common solid tumors in the world. Its global incidence is increasing and it has become the third leading cause of cancer-related deaths. There is growing evidence that chemokines play an important role in the tumor microenvironment, regulating the migration and localization of immune cells in tissues and are critical for the function of the immune system. This review comprehensively analyses the expression and activity of chemokines in the TME of HCC and describes their interrelationship with hepatocarcinogenesis and progression. Special attention is given to the role of chemokine-chemokine receptors in the regulation of immune cell accumulation in the TME. Therapeutic strategies targeting tumor-promoting chemokines or the induction/release of beneficial chemokines are reviewed, highlighting the potential value of natural products in modulating chemokines and their receptors in the treatment of HCC. The in-depth discussion in this paper provides a theoretical basis for the treatment of HCC. It is an important reference for new drug development and clinical research.

Keywords:  chemokines; hepatocellular carcinoma; immune intervention; natural products; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1456405