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Metabolic Reprogramming of Terminally Exhausted CD8+ T-cells by Interleukin-10 Enhances Anti-Tumour Immunity

ABSTRACT: Terminally exhausted CD8+ T-cells, which hold certain level of anti-tumour cytotoxicity but largely reduced proliferation capacity, contribute directly to tumour growth control. However, this subpopulation do not respond to immune checkpoint blockades or most existing immunotherapies and are difficult to be reactivated. Here, we show that a half-life extended interleukin (IL)-10/Fc fusion protein directly expands the terminally exhausted CD8+ TILs and sustains their effector functions through in vivo metabolic reprogramming, leading to eradication of established solid tumours and durable cures in a majority of treated mice when combined with adoptive T-cell transfer immunotherapy. Our results provide preclinical evidence that IL-10/Fc is a safe and highly effective therapy that acts on a specific subset of CD8+ TILs distinct from those responding to immune checkpoint blockades. Thus, IL-10/Fc could complement and synergize with existing cancer immunotherapies for enhanced efficacy and response rates. We find that IL-10/Fc reprograms T-cell metabolism by promoting oxidative phosphorylation through the mitochondrial pyruvate carrier, suggesting that metabolic reprogramming is sufficient to revitalize terminally exhausted CD8+ TILs.

ORGANISM(S): Mus musculus

PROVIDER: GSE168990 | GEO | 2021/04/01

REPOSITORIES: GEO

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Project description:In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, ex vivo treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after ex vivo IL-15 treatment compared with those before treatment revealed upregulation of ribosome-related genes and downregulation of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon ex vivo IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.

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Metabolic Reprogramming of Terminally Exhausted CD8+ T-cells by Interleukin-10 Enhances Anti-Tumour Immunity

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