Regulation and immunotherapy responses of NK cells (and T cells) against tumors

Most immunotherapy efforts aim to mobilize CD8+ T cells against cancer cells. Many tumors lack many neoantigens, and others are selected for partial or complete loss of MHC I, even before immunotherapy intervention.  Checkpoint immunotherapy further exacerbates this problem as it preferentially amplifies CD8 cytotoxic effector cell activity, which targets MHC I presented tumor epitopes, imposing strong selection for loss of MHC I or other antigen presentation functions. Natural killer (NK) cells target stress induced molecules on tumor cells and infected cells, and therefore do not depend on MHC expression. Instead, MHC engages inhibitory receptors on NK cells, meaning that MHC-deficiency in tumor cells renders them even more susceptible to NK mediated destruction. NK cells are also potentially advantageous as therapeutic targets, in that they are believed to mediate less toxicity than T cells. Other immune cells, including CD4 T cells may also target MHC I-deficient tumor cells, suggesting that a mixed immune response is more likely to be effective in eliminating tumors than one involving only CD8 T cells. Strategies to mount NK-mediated antitumor responses include mobilizing endogenous NK cells in cancer patients for direct tumor cell lysis or redirected lysis facilitated with bispecific antibodies, or NK cellular therapy for direct tumor cell lysis or lysis mediated by incorporated chimeric antigen receptors (CAR). Our recent research has employed STING agonists and IL-2 superkines to activate and sustain NK cell mediated antitumor activity. Employing MHC I-deficient tumor models, we find that STING agonist or superkines alone amplify antitumor effects mediated by NK cells, in some cases dramatically. The combination of the two was much more effective than either alone, however, even against the most recalcitrant tumor models. Notably, the same combination was highly effective in supporting tumor elimination by CAR-NK cells in preliminary studies, and was also highly effective in stimulating powerful CD8 and CD4 T cell responses against tumors. As a result, the combination was much more effective than checkpoint therapy in the mouse tumor models studied, including against tumor cells comprised of a mixture of MHC I+ and MHC I-deficient tumor cells, meant to mimic a tumor population under selection. This approach has promise for eliminating tumors and at the same time preventing outgrowth of variants with MHC I or other antigen-processing defects. Our research is currently focused on developing approaches to engineer NK cells to prevent intratumoral desensitization and prolong the effectiveness of NK cells for diverse cancer types.