{"doi":"10.1101/2021.01.27.21250464","title":"A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes","abstract":"Abstract Purpose A subset of primary prostate cancer (PCa) expresses programmed death-ligand 1 (PD-L1), but whether they have unique tumor immune microenvironment (TIME) or genomic features is unclear. Experimental Design We selected PD-L1-positive high-grade and/or high-risk primary PCa, characterized tumor-infiltrating lymphocytes (TILS) with multiplex immunofluorescence, and identified genomic alterations in immunogenic and non-immunogenic tumor foci. Results One-quarter of aggressive localized PCa cases (29/115) had tumor PD-L1 expression >5%. This correlated with increased density of CD8 + T cells, a large fraction co-expressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8 + PD-1 + cells did not express terminal exhaustion markers (TIM-3 or LAG-3), while a subset expressed TCF1. Consistent with these CD8 + PD-1 + TCF1 + cells being progenitors, they were found in antigen-presenting-cell niches in close proximity to MHC II + cells. CD8 T cell density in immunogenic PCa and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1 , were prevalent; the latter being strongly associated with a dendritic cell gene set in TCGA. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present. Conclusions A subset of localized PCa is immunogenic, manifested by PD-L1 expression and CD8 + T cell content comparable to RCC. The CD8 + T cells include effector cells and exhausted progenitor cells, which may be expanded by ICIs. Genomic losses of RB1, BRCA2 , and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of localized PCa patients. Statement of Translational Relevance Prostate cancer (PCa) is generally considered poorly immunogenic, with low expression of programmed death-ligand 1 (PD-L1) and low density of tumor-infiltrating immune cells. Accordingly, response rates to PD(L)-1 inhibition in unselected patients with advanced prostate cancer have been low. Here, we find that a substantial subset of aggressive primary PCa exhibits tumor PD-L1 expression and contains a high density of tumor-infiltrating lymphocytes. These lymphocytes contain sub-populations of exhausted progenitor CD8 + T cells and differentiated effector T cells, the hallmarks of ongoing anti-tumor immune response and a prerequisite for response to checkpoint inhibition. Furthermore, we identify genomic alterations that may be contributing to immunogenicity in these cases. These findings point to immune responses elicited in a subset of primary PCa, supporting the development of immune checkpoint blockade clinical trials in early-stage disease, such as biochemically recurrent PCa, that are driven by genomic features of the tumor or the immune microenvironment.","journal":"medRxiv","year":2021,"id":216349,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.935,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":240462,"name":"Miriam Ficial","orcid":"0000-0002-2005-9267","position":1,"is_corresponding":false},{"id":667012,"name":"Caroline S. Jansen","orcid":null,"position":2,"is_corresponding":false},{"id":620142,"name":"Taghreed Hirz","orcid":"0000-0001-9230-1756","position":3,"is_corresponding":false},{"id":665905,"name":"Luke del Balzo","orcid":"0000-0002-6341-6949","position":4,"is_corresponding":false},{"id":465474,"name":"Scott Wilkinson","orcid":"0000-0002-2613-8425","position":5,"is_corresponding":false},{"id":432700,"name":"Ross Lake","orcid":"0000-0002-6929-0793","position":6,"is_corresponding":false},{"id":665906,"name":"Anson T. Ku","orcid":"0000-0002-6471-5502","position":7,"is_corresponding":false},{"id":350319,"name":"Olga Voznesensky","orcid":"0000-0003-1033-0938","position":8,"is_corresponding":false},{"id":91625,"name":"David B. Sykes","orcid":"0000-0002-9788-0221","position":9,"is_corresponding":false},{"id":620144,"name":"Philip J. Saylor","orcid":"0000-0003-4849-3695","position":10,"is_corresponding":false},{"id":465480,"name":"Huihui Ye","orcid":"0000-0002-8307-9492","position":11,"is_corresponding":false},{"id":240995,"name":"Haydn Kissick","orcid":"0000-0001-7624-5598","position":12,"is_corresponding":false},{"id":240459,"name":"Sabina Signoretti","orcid":"0000-0002-5000-9105","position":13,"is_corresponding":false},{"id":465481,"name":"Adam G. Sowalsky","orcid":"0000-0003-2760-1853","position":14,"is_corresponding":false},{"id":85727,"name":"Steven P. Balk","orcid":"0000-0002-4546-7371","position":15,"is_corresponding":false},{"id":445670,"name":"David J. Einstein","orcid":"0000-0001-9163-3281","position":16,"is_corresponding":false},{"id":350321,"name":"Carla Calagua","orcid":"0000-0003-4438-8046","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:11.245932Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}