Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function

Abstract

The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of B7-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8 T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.

Genetic and clinical characterization of B7‐H3 (CD276) expression and epigenetic regulation in diffuse brain glioma

“…We also noticed that B7‐H3 expression was negatively associated with NK cell‐related immune response, consistent with the results reported by Lee et al. (2012) …”

PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

“…Preclinical studies suggested that combining PD-1 blockade with costimulatory agonists, immune checkpoint blockade (such as blockade of CTLA-4, 116 B7-H3, 53,117 CD270, 53 CD200R, 53,100 LAG-3, 60 or TIM-3 50,52,118 ), or other therapeutic agents (such as lenalidomide 53 Some combination trials have interim results available. Nivolumab and ipilimumab combination therapy had ORRs of 74% in HL and 20% in B-NHL in a phase 1 trial.…”

Cancer stemness, intratumoral heterogeneity, and immune response across cancers

“…Using both the CCLE and pan-cancer TCGA datasets, the expression of each of these genes was assessed in relation to our stemness signature (Figures 6C and 6D). This revealed positive associations between stemness and a number of immunoinhibitory genes, including CD276 (B7-H3, shown to inhibit T cell activation and autoimmunity (Lee et al, 2017), PVR (CD155, a member of the B7/CD28 superfamily, shown to exhibit potent inhibitory action in different subsets of immune cells (Mahnke and Enk, 2016), and TGFB1 (a key player in the induction of immunological tolerance (Johnston et al, 2016). Thus, the stemness phenotype involves the expression of several gene products that could potentially serve as targets for immune modulation.…”