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

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.