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RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumor immunity

ABSTRACT: RIG-I is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity remains unclear. Here, we demonstrate that RIG-I is upregulated in tumor infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T cell function and limit antitumor immunity. Mechanically, up-regulation of RIG-I in CD8+ T cells is induced by retinoic acid (RA), a metabolite of vitamin A in TME, and direct inhibits the AKT/glycolysis signaling pathway. In addition, deletion of RIG-I enhances the efficacy of adoptively transferred T cells against solid tumors and inhibition of RIG-I enhances the response to PD-1 blockade. Our findings identify RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with immune checkpoint blockade.

ORGANISM(S): Mus musculus

PROVIDER: GSE230045 | GEO | 2023/04/25

REPOSITORIES: GEO

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Project description:The concept of cancer immunosurveillance ascribes a role of cellular immunity in eliminating transformed cells with cytotoxic CD8+ T cells being a primary mediator. Cancer cells can express neoantigens to prime conventional CD8+ T cells which nonetheless transition to a dysfunctional state of exhaustion characterized by high expression of the immune checkpoint co-inhibitory receptor PD-1. Despite the clinical success of anti-PD-1 to revive cancer immunity, many patients do not respond to checkpoint blockade therapies. Of note, recent studies have revealed an incredible heterogeneity among tumor-infiltrating CD8+ T cells with the PD-1+ population being only a fraction, and yet, beside the PD-1+ subset, the identity of other populations of CD8+ T cells remains largely unknown. Here, in an unbiased survey of CD8+ T cells present in murine and human malignancies, we rediscovered a population of FCER1G+ innate-like T cells that we have previously shown to possess high cytotoxic potential and are resistant to exhaustion, hereon termed ‘killer innate-like T cells’, or ILTCks. While tumor-infiltrating CD8+PD-1+ T cells were oligoclonal, ILTCks were polyclonal with broad reactivity to unmutated tumor-associated antigens. ILTCks were not differentiated from conventional CD8+ T cells, but arose from ILTCk-committed progenitors following early encounter with cognate antigens during thymocyte development. Committed ILTCk thymic progenitors were continuously generated throughout life, and replenished the ILTCk compartment during tumor progression. Notably, expansion and effector differentiation of intratumoral ILTCks depended on high expression of IL-15 in cancer cells, and inducible activation of IL-15 signaling in adoptively transferred ILTCk progenitors suppressed tumor growth. Thus, antigen receptor self-reactivity and unconventional ontogeny distinguish ILTCks from CD8+PD-1+ T cells as a new class of tumor-elicited immune response. Strategies targeting ILTCks may enhance and complement current conventional CD8+ T cell-based cancer immunotherapies, in particular against tumors with low mutation burden or refractory to checkpoint blockade modalities.

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RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumor immunity

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