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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-03, Vol.121 (11), p.e2315989121-e2315989121
• Main Authors: Kar, Anwesha, Ghosh, Puspendu, Gautam, Anupam, Chowdhury, Snehanshu, Basak, Debashree, Sarkar, Ishita, Bhoumik, Arpita, Barman, Shubhrajit, Chakraborty, Paramita, Mukhopadhyay, Asima, Mehrotra, Shikhar, Ganesan, Senthil Kumar, Paul, Sandip, Chatterjee, Shilpak
• Format: Article
• Language: English
• Subjects: Ablation; AKT protein; Animals; Biological Sciences; Calcium (intracellular); Calcium channels; Calcium ions; Cancer; CD38 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell differentiation; Cytotoxicity; Differentiation; Effectiveness; Gene sequencing; Hepatocyte nuclear factor 1; Immunotherapy; Lymphocytes; Lymphocytes T; Malignancy; Mice; Molecular modelling; Neoplasms - drug therapy; Neoplasms - metabolism; PD-1 protein; Proto-Oncogene Proteins c-akt - metabolism; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; Sequence analysis; T-Lymphocyte Subsets - metabolism; Therapy; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2315989121

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 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.