B7-H3 as a Dual Clinically Relevant Checkpoint and Antibody Drug Conjugate Target Expressed Across Adenocarcinoma and Neuroendocrine Prostate Cancers
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".