Rogel et al. engineered the Fc domain of anti-human CD96 IgGs that inhibited CD96 binding to CD155 (also a TIGIT and CD226 ligand). Anti-CD3-induced T cell proliferation was co-stimulated by immobilized, FcγR-crosslinked, and soluble anti-CD96 IgG1s trans-crosslinked by FcγRI+ accessory cells. Functional, ELISA, and RNAseq analyses showed that anti-CD96 IgG1 directly costimulated T cell proliferation and effector function, and overcame Treg suppression. Anti-CD96 IgG1 costimulated TIL proliferation, and TGCA data showed that CD96 expression correlated with survival in HPV+ head and neck squamous cell carcinoma.

Contributed by Paula Hochman

ABSTRACT: New strategies that augment T-cell responses are required to broaden the therapeutic arsenal against cancer. CD96, TIGIT and CD226 are receptors that bind to a communal ligand, CD155, and transduce either inhibitory or activating signals. Whereas the function of TIGIT and CD226 is established, the role of CD96 remains ambiguous. Using a panel of engineered antibodies, we discovered that the T-cell stimulatory activity of anti-CD96 antibodies requires antibody crosslinking and is potentiated by Fc-gamma receptors. Thus, soluble 'Fc silent' anti-CD96 antibodies failed to stimulate human T cells, whereas the same antibodies were stimulatory after coating onto plastic surfaces. Remarkably, the activity of soluble anti-CD96 antibodies was reinstated by engineering the Fc domain to a human IgG1 isotype and was dependent on antibody trans-crosslinking by Fc-γRI. In contrast, neither human IgG2 nor variants with increased Fc-γ receptor IIB binding possessed stimulatory activity. Anti-CD96 antibodies acted directly on T cells and augmented gene expression networks associated with T-cell activation, leading to proliferation, cytokine secretion and resistance to regulatory T-cell suppression. Furthermore, CD96 expression correlated with survival in HPV+ head and neck squamous cell carcinoma and its crosslinking activated tumor-infiltrating T cells, thus highlighting the potential of anti-CD96 antibodies in cancer immunotherapy. .

Author Info: (1) School of Cancer Sciences, University of Southampton, Southampton, United Kingdom. (2) School of Cancer Sciences, University of Southampton, Southampton, United Kingdom. (3) Sc

Author Info: (1) School of Cancer Sciences, University of Southampton, Southampton, United Kingdom. (2) School of Cancer Sciences, University of Southampton, Southampton, United Kingdom. (3) School of Cancer Sciences, University of Southampton, Southampton, United Kingdom. (4) GenOway, GenOway, Lyon, France. (5) School of Cancer Sciences, University of Southampton, Southampton, United Kingdom. (6) Immunology, Bournemouth University, Poole, United Kingdom. (7) Emergence Tx, Emergence Tx France SAS, Marseille, France. (8) School of Cancer Sciences, University of Southampton, Southampton, United Kingdom. (9) School of Cancer Sciences, University of Southampton, Southampton, United Kingdom.