DOI: 10.1073/pnas.2315989121 ISSN: 0027-8424

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

Anwesha Kar, Puspendu Ghosh, Anupam Gautam, Snehanshu Chowdhury, Debashree Basak, Ishita Sarkar, Arpita Bhoumik, Shubhrajit Barman, Paramita Chakraborty, Asima Mukhopadhyay, Shikhar Mehrotra, Senthil Kumar Ganesan, Sandip Paul, Shilpak Chatterjee
  • Multidisciplinary

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.

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