Immunotherapeutic control of MHC I-heterogeneous tumors to minimize therapy resistance 2307892
The anti-tumor activity of CD8 T cells, which recognize MHC I-presented tumor antigens, is enhanced by blocking checkpoint receptors. Longitudinal tumor biopsies from patients with acquired resistance to anti-PD-1 therapy often reveal genetic deficiencies in antigen presentation or MHC I expression. The role of CD8 T cells in selecting for MHC I-deficiency has been inferred but never demonstrated. Defining causes of MHC I loss and approaches to prevent it are essential for improving the outcomes of cancer immunotherapy. To define immune cells responsible for selecting for outgrowth of MHC I-deficient tumors, we developed MHC I-mixed tumor models, applied immunotherapies, and depleted immune subsets. Tumor growth and composition (MHC I+ vs MHC I-) were determined. PD-1 blockade immunotherapy was poorly effective in mixed MHC I+/MHC I- tumor models and exerted potent selection mediated by CD8+ T cells for outgrowth of MHC I- cells. In contrast, IL-2 “superkines”, alone or in combination with STING agonists, were more effective and prevented outgrowth of MHC I- tumor cells in a manner dependent on multiple immune cell types. An alternative therapeutic approach in which Treg cells are depleted intratumorally also suppressed growth of both MHC I+ and MHC I- tumor cells, in this case largely independently of CD8 T cells. We demonstrated for the first time in a controlled setting with mixed MHC I+/- tumors that anti-PD-1 therapy selects for outgrowth of MHC I-deficient tumor cells, dependent on CD8 T cells. Outgrowth of MHC I-deficient cells was minimized and mixed tumors were better controlled with IL-2 “superkine” therapy, alone or in combination with a STING agonist, and intratumoral Treg depletion. Tumor control in those cases was mediated by multiple effector cell types. Thus, immunotherapies that drive mixed responses of CD8+ and CD4+ T cells and NK cells have the potential to minimize acquired resistance resulting from MHC I loss. NIH: R01CA270790 Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)