Shi et al. identified B7-H3 (encoded by CD276) as one of the most abundant checkpoints in PTEN/TP53-inactivated prostate cancer, and found that its expression was upregulated upon activation of Sp1, which is suppressed by PTEN/p53. In immunocompetent (but not NSG) mice, tumor or prostate-specific (GEMM model) elimination of CD276 increased T and NK cell infiltration and function, reduced MDSCs, and delayed tumor progression. In mouse models of PTEN/p53-deficient CRPC, the efficacy of a B7-H3 inhibitor was antagonized by increased Tregs and PD-L1, prompting combinations with anti-PD-L1 or anti-CTLA-4, which improved responses.
Contributed by Lauren Hitchings
ABSTRACT: Checkpoint immunotherapy has yielded meaningful responses across many cancers but has shown modest efficacy in advanced prostate cancer. B7 homolog 3 protein (B7-H3/CD276) is an immune checkpoint molecule and has emerged as a promising therapeutic target. However, much remains to be understood regarding B7-H3's role in cancer progression, predictive biomarkers for B7-H3-targeted therapy, and combinatorial strategies. Our multi-omics analyses identified B7-H3 as one of the most abundant immune checkpoints in prostate tumors containing PTEN and TP53 genetic inactivation. Here, we sought in vivo genetic evidence for, and mechanistic understanding of, the role of B7-H3 in PTEN/TP53-deficient prostate cancer. We found that loss of PTEN and TP53 induced B7-H3 expression by activating transcriptional factor Sp1. Prostate-specific deletion of Cd276 resulted in delayed tumor progression and reversed the suppression of tumor-infiltrating T cells and NK cells in Pten/Trp53 genetically engineered mouse models. Furthermore, we tested the efficacy of the B7-H3 inhibitor in preclinical models of castration-resistant prostate cancer (CRPC). We demonstrated that enriched regulatory T cells and elevated programmed cell death ligand 1 (PD-L1) in myeloid cells hinder the therapeutic efficacy of B7-H3 inhibition in prostate tumors. Last, we showed that B7-H3 inhibition combined with blockade of PD-L1 or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) achieved durable antitumor effects and had curative potential in a PTEN/TP53-deficient CRPC model. Given that B7-H3-targeted therapies have been evaluated in early clinical trials, our studies provide insights into the potential of biomarker-driven combinatorial immunotherapy targeting B7-H3 in prostate cancer, among other malignancies.
Author Info: (1) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (2) Department of Experimental Radiation Oncology, Univers
Author Info: (1) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (2) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (3) Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (4) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Department of Biology, Colby College, Waterville, ME 04901, USA. (5) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (6) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (7) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (8) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (9) Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (10) Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (11) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. (12) Tumor Angiogenesis Unit, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. (13) Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (14) Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
