Immune profiling of advanced prostate cancer harboring homologous recombination deficiency.
Bibliographic record
Abstract
163 Background: Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects up to 30% of patients with metastatic castrate-resistant prostate cancer (mCRPC) and is predictive of response to PARP inhibitors. The potential activity of ICI in this subset of patients is unknown and the tumour microenvironment (TME) associated with HRD is poorly understood. We used mPCa tumours of patients with known HRD alterations as a model to study clinically relevant, therapeutically targetable drivers of tumour immunology. Methods: Archival tumor tissue of patients with known germline or somatic HRD alterations enrolled in our institutional GU Biobank (n = 13) was used for immunohistochemistry to evaluate the expression of the following immune markers in both tumour cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (A2aR), GAL9, IL-2, LAG3, PD-L2, and TIM-3. The same markers were analyzed in untreated (n = 104), and neoadjuvant hormone therapy treated (NHT) (n = 16) tissue. Two-tailed t-test and Pearson R correlations were performed for analysis. Results: Among screened HRD alterations, BRCA1/2 were the most frequently identified ( BRCA1/2 n = 6, FANCC n = 1, FANCD2 n = 2, PALB2 n = 1, CDK12 n = 1, ATR n = 2). CD8+ cells were primarily localized in the stroma of HRD cohort specimens rather than in the glandular epithelia. The HRD cohort had higher levels of A2aR, in TC and SL (p≤0.0001 for both). When compared to the untreated cohort, PD-L2 levels were higher in SL of the HRD cohort (p≤0.05) while lower in the TC (p≤0.01). Lower levels of LAG3 were found in the HRD cohort TC compared to NHT cohort (p≤0.01). There were significantly lower levels of GAL9 in the TC of the HRD cohort compared to untreated (p < 0.0001) tumours. There were no differences in TIM-3 levels between the cohorts. Conclusions: Evaluation of stromal and tumour cell immune profiling indicates that compared to other subtypes, mPCa with HRD alteration have a unique immune profile abundant in CD8+ cell, and high in PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable pathways which may render clinical benefit in this patient population.
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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 | 0.001 | 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".