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