Therapeutic Targeting of Immune Evasion from the MICA - NKG2D Pathway

Dana-Farber Cancer Inst, Boston MA

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Abstract

Project Summary/Abstract 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, γδ T cells, NKT cells and NK cells, enabling elimination of stressed and transformed cells. Proteolytic shedding of MICA/B is a major immune evasion mechanism from NKG2D-mediated tumor immunity in human cancers. This shedding process involves unfolding of the MICA/B α3 domain by the disulfide isomerase ERp5 which renders it susceptible to cleavage by proteases of 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 designed antibodies that sterically block the shedding site in the MICA/B α3 domain. These antibodies potently inhibit MICA/B shedding by a diverse panel of human cancer cell lines and substantially increase the cell surface density of these stimulatory NKG2D ligands. Such MICA/B antibodies induce killing of human tumor cells by NK cells and elicit an immune response against metastatic disease in murine model systems. A mAb that inhibits MICA/B shedding is now being evaluated in a phase 2 clinical trial in patients with advanced cancer (NCT05117476). During the past funding period, we also developed a vaccine targeting the MICA/B α3 domain, which induces a CD4 and CD8 T cell response in addition to MICA/B α3 specific antibodies. Studies in a non-human primate model demonstrate that the vaccine induces high-titer antibodies specific for MICA/B and also provide preliminary evidence of vaccine safety. In Aim 1, we will investigate the mechanisms enabling efficacy of MICA/B-vax against tumors with important resistance mutations. A major advantage of MICA/B-vax is that it induces a dual T cell and NK cell mediated response against tumors. As a consequence, this vaccine remains efficacious against tumors resistant to cytotoxic T cells (B2m or Ifngr1 mutations). Efficacy against B2m-KO tumors is mediated by the coordinated action of CD4 T cells and NK cells: CD4 T cells enable recruitment of NK cells which then serve as the major effector cells. We will investigate the mechanisms by which CD4 T cells enable recruitment of NK cells into tumors using spatial technologies and genetic approaches. We will also define the effector mechanisms responsible for NK cell-mediated immunity. In Aim 2, we will study how MICA/B-vax enhances dendritic cell function within tumors and diversifies anti-tumor T cell responses. Preliminary data demonstrate that MICA/B-vax induces a substantial influx of DCs into tumors, particularly the cDC1 subpopulation critical for antigen cross-presentation to CD8 T cells. We will define the mechanisms responsible for enhanced cDC1 recruitment into tumors following MICA/B-vax and determine whether this vaccine enhances and diversifies neoantigen-specific T cell responses.