Tumor expressed BCAM impedes anti-tumor T cell immunity and can be targeted therapeutically

Abstract The significant albeit limited clinical benefit of therapeutic targeting of checkpoint inhibitors highlights the need for immunological understanding of cancer escape from anti-tumor immunity to develop novel and better therapeutics. We surmise that many protein-protein interactions that regulate T cell immunity have yet to be identified. Using human gain-of-function genetic screens, thousands of proteins were screened for their ability to inhibit primary human T cell function. B Cell Adhesion Molecule (BCAM) was identified as a potent inhibitor of T cell proliferation and cytotoxic T cell (CTL) ability to kill human tumors in vitro. Tumor cell surface BCAM inhibited anti-tumor immunity promoted tumor growth in vivo. Blockade with decoy soluble BCAM protein fused to a either a silenced or functional Fc domain (BCAM Fc fusion protein) was able to promote T cell anti-tumor immunity and reduce tumor growth in syngeneic and humanized CDX tumor models. Moreover, tumor BCAM interaction with known ligand Laminin-a5 (LAMA5) resulted in increased production of LAMA5 that was associated with ECM modifications and potent exclusion of T cells from the tumor microenvironment (TME). BCAM Fc disruption of BCAM-LAMA5 interactions resulted in decreased LAMA5 production, increased T cell infiltration and decreased tumor growth. These data support a multi-pronged role for BCAM in anti-tumor T cell suppression and exclusion that can be targeted therapeutically.