Therapeutic Targeting of Immune Evasion from the MICA - NKG2D Pathway

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Project Summary MICA and MICB (MICA/B) are stress proteins that are frequently expressed by diverse types of human cancer as a consequence of genomic damage, but are rarely expressed by healthy cells. MICA/B serve as ligands for the NKG2D receptor expressed by all cytotoxic lymphocytes, including CD8 T cells,  T cells, NKT cells and NK cells, enabling recognition and elimination of stressed and transformed cells. Proteolytic shedding of MICA/B is a major immune evasion mechanism from NKG2D-mediated tumor immunity in many human cancers. This shedding process involves unfolding of the MICA/B 3 domain by the action of the disulfide isomerase ERp5 which enables MICA/B cleavage by proteases belonging to the ADAM and MMP families. It is not feasible to inhibit shedding in vivo with small molecule inhibitors because the relevant proteases have broad substrate specificities. We developed an approach to inhibit MICA/B shedding by designing antibodies that sterically block the shedding site in the MICA/B 3 domain. These antibodies potently inhibit MICA/B shedding by a diverse panel of human cancer cell lines and thereby substantially increase the cell surface density of these stimulatory NKG2D ligands. As a consequence, MICA/B antibodies induce strong killing of human tumor cells by NK cells. These antibodies also induce immunity in mouse models of metastasis. Single-cell RNA-seq data show that a MICA/B antibody induces a striking shift among metastasis-infiltrating NK cells to an activated and cytotoxic state. We have also validated these antibodies in a humanized mouse model in which human NK cells target metastases formed by human tumor cells. Many human cancers are resistant to immunotherapy with checkpoint blockade through loss of MHC class I expression. However, MHC class I protein expression is not required for anti-tumor immunity mediated by innate T cell populations (NKT cells, T cells) and NK cells that all express the NKG2D receptor. The major goal of this project is to develop MICA/B antibodies as a therapeutic strategy for MHC class I deficient tumor cells that are resistant to conventional CD8 T cells. We have developed an integrated approach to study this important question in fully immunocompetent mouse models (Aim 1) as well as humanized mouse models and human tumor metastases (Aim 2). In Aim 1, we will examine the contribution of innate T cell and NK cell populations to MICA/B antibody mediated immunity against spontaneous metastases. In Aim 2, we will perform an in depth single-cell RNA-seq analysis of NKG2D-expressing innate T cell and NK cell population in human melanoma metastases. We will also use a humanized mouse model to develop combination therapies with established cancer therapeutics that enhance MICA/B expression and may therefore act synergistically with MICA/B antibodies. These studies will significantly advance the cancer immunotherapy field by developing novel approaches to target human cancers resistant to current immunotherapies.