Tumor-Associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers

细胞毒性T细胞 CD8型 免疫疗法 生物 癌症研究 癌症免疫疗法 免疫系统 肿瘤微环境 免疫检查点 T细胞 白细胞介素21 免疫学 体外 生物化学
作者
No‐Joon Song,Juan Xie,Kyeong Joo Jung,Yi Wang,Joanna Poźniak,Niccolò Roda,Jean‐Christophe Marine,Brian Riesenberg,Hyeongseon Jeon,Anjun Ma,Nigel Cox,Darren Wethington,Kelsi Reynolds,Tong Xiao,Anqi Li,Parker Kronen,Nicholas Denko,David P. Carbone,Qin Ma,William E. Carson
出处
期刊:Cancer Discovery [American Association for Cancer Research]
卷期号:: OF1-OF23
标识
DOI:10.1158/2159-8290.cd-24-1232
摘要

Abstract Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis represent established therapies for many cancers. However, resistance occurs in most patients due to complex immune-suppressive mechanisms in the tumor microenvironment. NK cells can play effector roles in tumor control, but their impact on T-cell dysfunction and ICB efficacy remains controversial. Through genetic and antibody-mediated NK cell depletion, we found that a subset of tumor-associated NK cells plays a negative role in ICB sensitivity; they further impede CD8+ T-cell differentiation toward a CD69+ BCL2+ EOMES+ GZMB+ TIM3− GITR− phenotype. Mechanistically, the retinoic acid receptor α–dependent differentiation program in CD8+ T cells is hindered by tumor-infiltrating NK cells via competition for IFNα and IL-2. Finally, we observed that lower frequencies of NK cells correlate with better clinical responses to ICBs in patients with cancer. These findings suggest potential avenues for enhancing CD8+ T cell–centered immunotherapy by targeting regulatory NK cells. Significance: Although NK cells are traditionally viewed as antitumor effectors, our study uncovers their unexpected suppressive role in CD8+ T cell–based immunotherapy. By competing for cytokines, they disrupt retinoic acid receptor α–driven CD8+ T-cell differentiation and limit ICB efficacy. Clinically, reduced NK cell presence is associated with an enhanced immunotherapy response. See related article by Pozniak et al. p. XX
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