Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies

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.

Expanding horizons in overcoming therapeutic resistance in castration-resistant prostate cancer: targeting the androgen receptor-regulated tumor immune microenvironment

“…Immune checkpoints, such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), play crucial roles in maintaining immune homeostasis. In CRPC, the upregulation of immune checkpoint molecules, including B7-H3, contributes to immune evasion and resistance to immune-based therapies 11 , 12 . Consequently, targeting these checkpoint molecules with immune checkpoint inhibitors has shown promising results in clinical trials, thereby highlighting the value of immune modulation in CRPC treatment.…”

Exploiting the DNA Damage Response for Prostate Cancer Therapy

“…The expression of B7-H3 was high in many PCa patient samples and cell lines, notably, higher than PD-L1 (B7-H1), and it correlated with adverse disease events [ 227 , 228 ]. The modulation of B7-H3 levels in multiple cell types, including PTEN-TP53 -deficient CRPC, impaired tumor growth [ 229 ]. As PD-L1 expression is activated by RT and other DNA-damaging agents, it will be of interest to determine if B7-H3 levels can be similarly manipulated for clinical gain, for example by RPT or ATR/PARP inhibitors.…”

Causal relationship between immune cells and prostate cancer: a Mendelian randomization study

“…Increasing research indicates that immune cells were involved in the development of prostate cancer. Various cell types involved in the regulation of prostate cancer have been identified ( Fridlender et al, 2009 ; Sagnak et al, 2011 ; Shi et al, 2023 ). NK cells and CD8 + T lymphocytes are pivotal forces in anti-tumor immunity, effectively eliminating cancer cells.…”

“…NK cells and CD8 + T lymphocytes are pivotal forces in anti-tumor immunity, effectively eliminating cancer cells. Conversely, tumor-associated macrophages and other cells exert inhibitory effects on anti-tumor immunity, and their excessive activation may be associated with the occurrence and progression of tumors ( Luo et al, 2021 ; Shi et al, 2023 ). While there is a preliminary understanding of the roles of certain immune cell types in the pathogenesis of prostate cancer, the specific functions of various subtypes of immune cells and whether there is a causal relationship between these cells and tumor development remain unclear.…”