B7-H3 as a Dual Clinically Relevant Checkpoint and Antibody Drug Conjugate Target Expressed Across Adenocarcinoma and Neuroendocrine Prostate Cancers

Abstract Background and Objectives CD276 (B7-H3) has recently emerged as a promising presumptive immune checkpoint inhibitor (ICI) and a potential antibody-drug conjugate (ADC) target for prostate cancer (PCa). We evaluated B7-H3 and 15 other clinically relevant ADC and ICI targets for expression at the RNA and protein level across the PCa continuum—hormone-sensitive, castration-resistant, and neuroendocrine. Methods CCLE data analysis and western blot experiments were performed for quantifying RNA and protein expression variability across PCa cell lines. Inter- and intratumoral heterogeneity was evaluated by integrating single-cell RNA sequencing data across 595k cells and 102 patients, spanning the disease continuum. AR and B7-H3 knockouts of PCa cell lines were developed and investigated using R1881 and Enzalutamide to elucidate the AR-CD276 signaling pathway through qRT-PCR and flow cytometry. Key Findings B7-H3 showed high expression in tumor and myeloid cells (tumor microenvironment – TME), lowest heterogeneity across all ADC and ICI targets, and was negatively regulated by androgen signaling. Limitations Further validation of ADC and ICI target protein expression in human samples and more exhaustive exploration of the AR-CD276 signaling cascade is required. Conclusion B7-H3 demonstrates the least susceptibility to selective pressure due to its stable expression across PCa disease states. Clinical Implications B7-H3 represents an important ADC target for PCa due to its potential to minimize drug resistance and likely ability to be a valid target across the prostate cancer continuum. Additionally, its expression in myeloid cells supports a dual role as an ICI, further enhancing its therapeutic relevance. Graphical Abstract Discovery of optimal checkpoints and antibody drug conjugates (ADCs) in Prostate Cancer (PCa). Patient Summary In this study, we demonstrate that prostate cancer expresses high amounts of a cell surface protein called B7-H3 both when first diagnosed and throughout various stages of metastatic disease. Furthermore, we demonstrate a clear and yet to be fully resolved cross-talk between B7-H3 and the androgen signaling pathway central to prostate cancer development. We conclude that B7-H3 is therefore a highly promising therapeutic cell surface protein expressed by prostate cancer due to its stable expression potentially leading to low selective pressure and reduced drug resistance—thereby having significant implications for clinical trial design and patient inclusion considerations. Advancing Practice PCa is a highly heterogeneous disease with an increasingly wide treatment landscape, governed by various factors including clinical covariates, histopathological features, and molecular factors. B7-H3 has recently emerged as a promising clinical target for immunotherapy in the localized setting and antibody drug targeting in the metastatic setting. Despite the clinical significance, B7-H3 expression has not yet been thoroughly evaluated against other clinically relevant immune checkpoint and antibody drug targets, especially along the continuum of PCa treatment stages—hormone sensitive, castration resistant, and neuroendocrine. To our knowledge, this is the first study to characterize B7-H3 in this continuum using representative cell lines and the largest collection of PCa patient single cell sequencing data yet assembled in the literature, thus accounting for the substantial heterogeneity across PCa disease states as well as between datasets. Take Home Message This article explores the therapeutic relevance of clinical stage ADC targets and immune checkpoints for Prostate Cancer (PCa). We show that B7-H3 is a highly promising therapeutic candidate for PCa due to its stable expression across various disease states.

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