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Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness.

ABSTRACT: Only a subset of cancer patients responds to checkpoint blockade inhibition in the clinic. Strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) has shown efficacy in preclinical models, but GITR engagement is ineffective in controlling advanced, poorly immunogenic tumors, such as B16 melanoma, and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) depletes regulatory T cells (Tregs), expands tumor-specific effector T cells (Teffs) via homeostatic proliferation, and induces immunogenic cell death. GITR agonism has an inhibitory effect on Tregs and activates Teffs. We therefore hypothesized that CTX and GITR agonism would promote effective antitumor immunity. Here we show that the combination of CTX and GITR agonism controlled tumor growth in clinically relevant mouse models. Mechanistically, we show that the combination therapy caused tumor cell death, clonal expansion of highly active CD8+ T cells, and depletion of Tregs by activation-induced cell death. Control of tumor growth was associated with the presence of an expanded population of highly activated, tumor-infiltrating, oligoclonal CD8+ T cells that led to a diminished TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemoimmunotherapeutic approach that warrants further clinical investigation.

SUBMITTER: Hirschhorn D

PROVIDER: S-EPMC8564916 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness.

Hirschhorn Daniel D Betof Warner Allison A Maniyar Rachana R Chow Andrew A Mangarin Levi Mb LM Cohen Adam D AD Hamadene Linda L Rizzuto Gabrielle A GA Budhu Sadna S Suek Nathan N Liu Cailian C Houghton Alan N AN Merghoub Taha T Wolchok Jedd D JD

JCI insight 20211022 20

Only a subset of cancer patients responds to checkpoint blockade inhibition in the clinic. Strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) has shown efficacy in preclinical models, but GITR engagement is ineffective in controlling advanced, poorly immunogenic tumors, such as B16 melanoma, and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) deplete ...[more]

PMID: 34676831

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Project description:BackgroundImmunotherapy that targets immune checkpoints has achieved revolutionary success, but its application in solid tumors remains limited, highlighting the need for reliable enhancement of the efficacy of immunotherapy. Golgi protein 73 (GP73), a Golgi membrane protein, has been implicated in various cellular processes, including immune regulation. Recent studies suggested that GP73 may play a role in modulating the immune response in patients with cancer. In this study, we investigated the mechanism by which GP73 regulates T-cell-mediated antitumor immunity within the tumor microenvironment.MethodsWe used T-cell specific GP73 knockout mice to establish MC38 and B16 tumor models to investigate the impact of GP73-deficient T cells on tumor growth. Single-cell sequencing was subsequently employed to classify tumor-infiltrating immune cells and assess changes in cytokines and metabolic genes. Through RNA sequencing, real-time quantitative PCR, western blotting, flow cytometry, seahorse analysis, glucose uptake, and L-lactic acid secretion assays, we explored how GP73 regulates hypoxia-inducible factor 1α (HIF-1α) to influence T-cell antitumor functionality. Furthermore, we established adoptive transfer experiments to study the ability of GP73-overexpressing T cells to combat tumors. Blood samples of patient with clinical tumor were collected to assess the relationship between immunotherapy efficacy and T-cell GP73 levels.ResultsIn this study, the absence of GP73 in mouse T cells promoted tumor growth and metastasis, accompanied by a decrease in the proportion of cytotoxic CD8+T cell subsets infiltrating the tumor and an increase in exhausted CD8+ T-cell subsets. Further analysis revealed that the effector function of CD8+T cells in tumors relies on glycolysis regulated by HIF-1α rather than immune checkpoints. GP73-deficient T cells exhibit severely impaired glycolysis in hypoxic environments, whereas ectopic GP73 expression restores HIF-1α levels. In adoptive immunotherapy, overexpression of GP73 in T cells inhibits tumor growth. In cytotoxicity assays, knockdown of GP73 affected the ability of CD8+T cells to kill target cells. Clinically, tumor immunotherapy partial response patients present significantly elevated levels of GP73 expression in T cells.ConclusionsThese findings reveal the role of GP73 in regulating T-cell glycolysis and may lead to new therapeutic strategies for the prognosis and treatment of clinical tumor immunotherapy.

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Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness.

Publications

Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness.

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