The crosstalk of CD8+ T cells and ferroptosis in cancer

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 15, 2024

Ferroptosis is an iron-dependent, novel form of programmed cell death characterized by lipid peroxidation and glutathione depletion widespread in a variety diseases. CD8+ T cells are the most important effector cytotoxic cells, capable specifically recognizing killing cancer cells. Traditionally, thought to induce mainly through perforin granzyme, Fas-L/Fas binding. In recent years, cell-derived IFN-γ was found promote ferroptosis multiple mechanisms, including upregulation IRF1 IRF8, downregulation system XC-, while shown enhance anti-tumor effects heating tumor immune microenvironment exposure release tumor-associated specific antigens, which results positive feedback pathway. Unfortunately, intra-tumoral more sensitive than limits application inducers cancer. addition, susceptible being regulated other TME, such as macrophages, dendritic Treg, bone marrow-derived immunosuppressive Together, these factors build complex network Therefore, we aim integrate relevant studies reveal potential mechanisms crosstalk between ferroptosis, summarize preclinical models therapy find new therapeutic strategies this review.

Language: Английский

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Potential crosstalk between SPP1 + TAMs and CD8 + exhausted T cells promotes an immunosuppressive environment in gastric metastatic cancer

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 16, 2024

Abstract Background Immunotherapy brings new hope to patients with advanced gastric cancer. However, liver metastases can reduce the efficacy of immunotherapy in patients. Tumor-associated macrophages (TAMs) may be cause this reduction efficacy. SPP1 + TAMs are considered have immunosuppressive properties. We aimed investigate involvement metastasis Methods The single-cell transcriptome was combined batched BULK datasets for analysis. Animal models were used verify analysis results. Results reveal interaction CD8 exhausted T cells metastatic Among these interactions, GDF15-TGFBR2 play a key role. constructed an LR score quantify interactions based on ligands and receptors. is highly correlated various immune features clinical molecular subtypes. also guide prediction prognosis. Conclusions crosstalk between plays role cancer microenvironment. Graphical

Language: Английский

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LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation

Molecular Therapy, Journal Year: 2022, Volume and Issue: 30(8), P. 2800 - 2816

Published: May 6, 2022

Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory receptor involved in T exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 PD-L1 modulating responses against tumors. ABL501 efficiently inhibits both pathways enhances the activation effector CD4

Language: Английский

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Role of T cells in cancer immunotherapy: Opportunities and challenges

Cancer Pathogenesis and Therapy, Journal Year: 2022, Volume and Issue: 1(2), P. 116 - 126

Published: Dec. 20, 2022

Immunotherapies boosting the immune system's ability to target cancer cells are promising for treatment of various tumor types, yet clinical responses differ among patients and cancers. Recently, there has been increasing interest in novel immunotherapy practices aimed at triggering T cell-mediated anti-tumor responses. Antigen-directed cytotoxicity mediated by lymphocytes become a central focal point battle against utilizing system. The molecular cellular mechanisms involved actions have directed new therapeutic approaches immunotherapy, including checkpoint blockade, adoptive chimeric antigen receptor (CAR) cell therapy, vaccinology. This review addresses all strategies targeting pathogenesis, metabolic pathways, evaluate significance current future immunotherapies with cancer, which further engaged activation, differentiation, response tumors.

Language: Английский

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Radiation-induced PD-L1 expression in tumor and its microenvironment facilitates cancer-immune escape: a narrative review

Annals of Translational Medicine, Journal Year: 2022, Volume and Issue: 10(24), P. 1406 - 1406

Published: Dec. 1, 2022

Background and Objective: Radiotherapy (RT) is one of the fundamental anti-cancer regimens by means inducing in situ tumor vaccination driving a systemic anti-tumor immune response. It can affect microenvironment (TME) components consisting blood vessels, immunocytes, fibroblasts, extracellular matrix (ECM), might subsequently suppress immunity through expression molecules such as programmed death ligand-1 (PD-L1). Immune checkpoint inhibitors (ICIs), especially anti-programmed cell 1 (PD-1)/PD-L1 therapies, have been regarded effective reinvigoration system another major cancer treatment. Experimentally, combination RT ICIs therapy shows greater synergistic effect than either alone. Methods: We performed narrative review literature PubMed database. The research string comprised various combinations "radiotherapy", "programmed death-ligand 1", "microenvironment", "exosome", "myeloid cell", "tumor immunity". database was searched independently two authors. A third reviewer mediated any discordance results screeners. Key Content Findings: upregulates PD-L1 cells, tumor-derived exosomes (TEXs), myeloid-derived suppressor cells (MDSCs), macrophages. signaling pathways correlated to include DNA damage pathway, epidermal growth factor receptor (EGFR) interferon gamma (IFN-γ) cGAS-STING JAK/STATs pathway. Conclusions: upregulation post-RT found not only but also TME mechanisms evasion. Therefore, further studies are necessary fully comprehend this biological process. Meanwhile, therapies has shown be effective, novel approaches developed adjuvant therapy.

Language: Английский

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Targeting CD96 overcomes PD-1 blockade resistance by enhancing CD8+ TIL function in cervical cancer

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(3), P. e003667 - e003667

Published: March 1, 2022

Novel therapies are needed to treat recurrent and advanced cervical cancer (CC), as their prognosis remains very poor. Although targeting the programmed cell death protein 1 (PD-1) pathway have been approved for CC, a large subset of patients exhibit innate resistance. Using checkpoint inhibitors in combination could enhance efficacy.Blood samples, tumor specimens, peritumorous (PT) tissues were obtained from with CC. The inhibitory receptor expression phenotypical analysis CD8+ T cells CC specimens analyzed by flow cytometry. ligands CD96 expressed measured immunohistochemistry immunofluorescence. Sensitivity pembrolizumab was evaluated an ex vivo treatment assay based on single-cell culture specimens. efficacies PD-1 and/or blockades explored using human papillomavirus-positive TC-1 xenograft mouse model vivo.We found that elevated tumor-infiltrating lymphocytes (TILs) who insensitive blockade. These CD96-expressing TILs often coexpressed PD-1. ratio CD96+CD8+/CD96-CD8+ T-cell gene signature scRNA-seq data significantly associated poor survival squamous carcinoma endocervical adenocarcinoma. costimulatory CD226, which competes CD96, downregulated tumors compared blood PT tissue. immunoreceptor Ig ITIM domains (TIGIT) upregulated intratumoral cells. CD226/CD96/TIGIT signaling widely tissues. Phenotypical profiling showed PD-1+CD96+CD8+ exhibited terminally exhausted effector phenotype high levels immunoglobulin mucin 3 (TIM-3) granzyme B (GZMB) extremely low proinflammatory cytokines cytotoxic molecules. PD-1+CD96 precursor TCF-1 positivity. further Treatment blockade enhanced blunt growth improve function both specimen models.Our findings cooperatively negatively regulate TILs, has promise use

Language: Английский

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The current state and future of T-cell exhaustion research

Oxford Open Immunology, Journal Year: 2023, Volume and Issue: 4(1)

Published: Jan. 1, 2023

Abstract ‘Exhaustion’ is a term used to describe state of native and redirected T-cell hypo-responsiveness resulting from persistent antigen exposure during chronic viral infections or cancer. Although well-established phenotype across mice humans, exhaustion at the molecular level remains poorly defined inconsistent literature. This is, in part, due an overreliance on surface receptors define these cells explain exhaustive behaviours, incomplete understanding how arises, lack clarity over whether same contexts, e.g. versus With development systems-based genetic approaches such as single-cell RNA-seq CRISPR screens applied vivo data, we are moving closer consensus view exhaustion, although it arises challenging given difficulty manipulating setting. Accordingly, producing studying exhausted T-cells ex burgeoning, allowing experiments be conducted scale up with high throughput. Here, first review what currently known about it’s being studied. We then discuss improvements their method isolation/production examining impact different microenvironmental signals cell interactions have now become active area research. Finally, future holds for analysis this physiological condition and, diversity ways which generated, propose adoption unified approach clearly defining using set metabolic-, epigenetic-, transcriptional-, activation-based phenotypic markers, that call ‘M.E.T.A’.

Language: Английский

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Towards a consensus definition of immune exclusion in cancer

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: March 22, 2023

Background The immune cell topography of solid tumors has been increasingly recognized as an important predictive factor for progression disease and response to immunotherapy. distribution pattern cells in is commonly classified into three categories - namely, “ Immune inflamed ”, desert” “Immune excluded” which, some degree, connect presence positioning within the tumor microenvironment anti-tumor activity. Materials methods In this review, we look at ways exclusion defined published literature identify opportunities develop consistent, quantifiable definitions, which turn, will allow better determination underlying mechanisms that span cancer types and, ultimately, aid development treatments target these mechanisms. Results definitions phenotypes, especially exclusion, have largely conceptual. existing lacks consistency when it comes practically defining there no consensus on a definition. Majority use somewhat arbitrary cut-offs attempt place each distinct phenotypic category. Tumor heterogeneity often not accounted for, limits practical application Conclusions We identified two key issues establishing clinically relevant spectrum infiltration well heterogeneity. propose approach overcome limitations, by reporting degree infiltration, tying meaningful outcome measures, maximizing number regions are analyzed This definition operationalizing categorization clinical trial signal-seeking endpoints.

Language: Английский

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Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(17)

Published: Aug. 31, 2023

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited the subset of cancers thought possess a sufficient tumor mutational burden (TMB) allow for spontaneous recognition neoantigens (NeoAg) by autologous T cells. We explored whether response ICB an aggressive low-TMB squamous cell could be improved through combination immunotherapy using functionally defined NeoAg as targets endogenous CD4+ and CD8+ found that, whereas vaccination with or alone did not offer prophylactic therapeutic immunity, vaccines containing recognized both subsets overcame resistance led eradication large established tumors that contained PD-L1+ tumor-initiating cancer stem cells (tCSC), provided relevant epitopes were physically linked. CD4+/CD8+ produced modified microenvironment (TME) increased numbers NeoAg-specific existing in progenitor intermediate exhausted states enabled ICB-mediated intermolecular epitope spreading. believe concepts herein should exploited development more potent personalized can expand range treatable ICB.

Language: Английский

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Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Oct. 25, 2023

Abstract T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term control pathogens. In response to strong stimulation, as seen in severe or chronic infections cancer, cells acquire state hypo-responsiveness known exhaustion, limiting their function. Recent advances autologous chimeric antigen receptor (CAR)-T therapies have revolutionized treatment hematologic malignancies by taking advantage basic principles biology engineer products that promote long-lasting response. However, many patients’ remain unresponsive are prone recur. Discoveries biology, including identification key regulators offer novel opportunities durable impact on fate CAR-T after infusion. Such next-generation clinical implementation may result next leap forward cancer selected patients. this context, review summarizes foundational exhaustion describes how they can be utilized targeted further improve design efficacy therapies.

Language: Английский

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