CD38–RyR2 axis–mediated signaling impedes CD8 ⁺ T cell response to anti-PD1 therapy in cancer

Abstract

PD1 blockade therapy, harnessing the cytotoxic potential of CD8 + T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8 + T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8 + T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8 + T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8 + T cells, revealed that CD38-expressing CD8 + T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8 + T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8 + T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8 + T cells elevated intracellular Ca 2+ levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8 + T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer.

Deletion of CD38 enhances CD19 chimeric antigen receptor T cell function

“… 24 Moreover, CD38 is postulated to modulate the T cell response through the RyR2 axis, enhancing calcium signaling and reducing the expression of transcription factors like TCF1. 25 Tumor-infiltrating CD4 T cells that express CD38 and CD39 are distinct from regulatory T cells (Tregs) but can also inhibit the proliferation of bystander T cells, suggesting that ectoenzyme activity can function in a cell-extrinsic manner. 26 , 17 …”