The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

Effective immune responses to cancer rely on the ability of tumour-infiltrating lymphocytes (TILs) to overcome the immunosuppressive obstacles that are present in the tumour microenvironment.

Inhibitor molecules which are highly upregulated on TILs, such as programmed death-1 (PD-1) or cytotoxic T lymphocyte antigen 4 (CTLA-4), are proving to be successful targets for boosting the anti-tumour immune response.

Scharping and colleagues identified a PD-1 and CTLA-4 independent mechanism of T cell suppression. Using an immune-intact B16 syngeneic mouse model, their findings show that T cells infiltrating tumours, but not in the periphery, are metabolically insufficient.

The persistent loss of mitrchondrial function is due to the repression of PPAR-gamma coactivator 1α (PGC1α) expression on T cells, and overexpression of PGC1α in T cells resulted in a regain of metabolic activity and mitochondrial function. Transfer of T cells overexpressing PGC1α was therapeutic in B16 tumour-bearing mice.

The findings in this paper highlight that the metabolic pathway of TILs may provide a novel immune pathway to target for cancer immunotherapy.

Scharping et al. (2016). The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. Immunity 136(8): 1692-1700

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Epistem - 3 validated mouse models for immune function

At Epistem, we currently offer 3 models to address the immune response in tumour bearing mice.

Metabolic and mitochondrial function of T cells can be assessed by flow cytometry.

Our detailed flow cytometric expertise can further assess the identity of tumour infiltrating and peripheral cell populations, by surface identification of key molecules, or the intracellular mediators they express (cytokines, transcription factors).

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