Natural killer cells subvert immune checkpoint therapy of tumors

Since natural killer (NK) cells can kill tumor cells that also stimulate NK cell production of cytokines, there is intense current interest on how to harness NK cells to advance immunotherapy of cancer. Most strategies guiding such work focus on markedly enhancing NK cell responses to tumors. However, our understanding of NK cell biology in the context of immune checkpoint therapy (ICT) of cancer is poorly understood. Contrary to expectations, here the applicant’s laboratory presents preliminary data indicating that antibody-mediated NK cell depletion or genetic absence of NK cells enhanced ICT in mice, suggesting NK cells subvert ICT. Moreover, transfer of NK cells into the tumor itself in mice genetically lacking NK cells restored subversion of ICT. Furthermore, anti-NKG2D also enhanced ICT. Finally, the applicant provides evidence from human tumor databases that a similar process may be occurring in patients. Thus, NK cells subvert ICT and NKG2D appears to be involved in this process. Therefore, the Specific Aims of this proposal are to: 1) Elucidate effector mechanism(s) by which NK cells constrain ICT; 2) Evaluate contribution of NKG2D; and 3) Translate mouse findings to human tumors. Taken together, this proposal will lead to increased insight on the role of NK cells in ICT and will help guide new strategies to modulate NK cells for improved cancer immunotherapy. Project Number: 1R01CA303538-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Wayne Yokoyama | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $3,182,665 | Activity Code: R01 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11205003