Data from Tumor-associated NK Cells Regulate Distinct CD8<sup>+</sup> T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers

<div>Abstract<p>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<sup>+</sup> T-cell differentiation toward a CD69<sup>+</sup> BCL2<sup>+</sup> EOMES<sup>+</sup> GZMB<sup>+</sup> TIM3<sup>−</sup> GITR<sup>−</sup> phenotype. Mechanistically, the retinoic acid receptor α–dependent differentiation program in CD8<sup>+</sup> 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<sup>+</sup> T cell–centered immunotherapy by targeting regulatory NK cells.</p>Significance:<p>Although NK cells are traditionally viewed as antitumor effectors, our study uncovers their unexpected suppressive role in CD8<sup>+</sup> T cell–based immunotherapy. By competing for cytokines, they disrupt retinoic acid receptor α–driven CD8<sup>+</sup> T-cell differentiation and limit ICB efficacy. Clinically, reduced NK cell presence is associated with an enhanced immunotherapy response.</p><p><a href="https://aacrjournals.org/cancerdiscovery/article-abstract/doi/10.1158/2159-8290.CD-25-1042" target="_blank"><i>See related commentary by Galvez-Cancino et al., p. 1777</i></a></p><p><a href="https://aacrjournals.org/cancerdiscovery/article-abstract/doi/10.1158/2159-8290.CD-24-1208" target="_blank"><i>See related article by Pozniak et al., p. 1819</i></a></p></div>