Global inhibition of Ly-49/MHC-I interactions by anti-MHC-I augments innate and adaptive immunity against cancer metastasis.

Abstract

Abstract We have identified an pan-anti-MHC-I mAb (M1/42), which blocks the interaction of NK cell inhibitory receptors (Ly-49 antigens) with MHC-I, but does not inhibit antigen presentation by MHC-I. Administration of M1/42 in vivo markedly activated IFNg-producing NK cells. NK cell-derived IFNg stimulated APC to produce IL-12/-15/-18 cytokine cascades that further drove the proliferation of NK cells and memory phenotype (MP) T cells. M1/42 treatments profoundly augmented innate and adaptive immunity against PD-1-sensitive and -resistant transplanted tumors. Given that NK cells are critical to control of cancer metastases, we evaluated the effects of M1/42 therapy in several metastatic cancer models. M1/42 treatments successfully constrained B16F10 lung metastasis by enhancing CD8 +T cell infiltration and inducing melanoma-specific MP CD8 +T cell expansion and activation. In contrast, treatment with conventional checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4 and anti-NKG2A) had no therapeutic effect. scRNAseq analysis of B16F10 lung melanoma tumor infiltrating lymphocytes revealed that M1/42 treatment significantly enhanced the expression of multiple genes associated with NK cell proliferation and activation. M1/42 also enhanced Th1-type innate and adaptive immune responses, and greatly restricted liver and lung metastasis produced by pancreatic adenocarcinoma cell line via intrasplenic or intravenous injection. Thus, the global inhibition of Ly-49/MHC-I interactions by M1/42 results in activation of a potent innate and adaptive immune response that restrains the growth of both transplanted tumors and cancer metastasis produced by intrasplenic or intravenous injection of tumor cells. This work was supported by the Intramural Research Program of NIAID, NIH.