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

• 成果类型: Article
• 署名作者: Kara, Anwesha; Ghosha, Puspendu; Gautamc, Anupam; Chowdhurya, Snehanshu; Basaka, Debashree; Sarkara, Ishita; Bhoumika, Arpita; Barmanb, Shubhrajit; Chakrabortyf, Paramita; Mukhopadhyayg, Asima; Mehrotraf, Shikhar; Ganesane, Senthil Kumar; Paulh, Sandip; Chatterjeea, Shilpak
• 署名单位: Council of Scientific & Industrial Research (CSIR) - India; CSIR - Indian Institute of Chemical Biology (IICB); Academy of Scientific & Innovative Research (AcSIR); Eberhard Karls University of Tubingen; Council of Scientific & Industrial Research (CSIR) - India; CSIR - Indian Institute of Chemical Biology (IICB); Medical University of South Carolina
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10945
• DOI: 10.1073/pnas.2315989121
• 发表日期: 2024-03-07
• 关键词: dysfunction; subsets; STATES; lymphocytes; activation; mechanisms; expansion

摘要

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 Ca2+ 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.