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Background The prostate tumor microenvironment is highly immunosuppressive, with few intratumoral effector T cells and high density of suppressive immune cell subsets, cytokines, and signaling pathways. Although two phase III clinical trials of anti-CTLA-4 monotherapy in metastatic castration-resistant prostate cancer (mCRPC) failed to demonstrate a survival benefit, a subset of patients derived clinical benefit. 1–3 We previously showed that increased intratumoral CD8 T cell density, IFN-γ response gene signatures, and antigen-specific T cell responses were associated with favorable clinical outcomes with ipilimumab.4 Tertiary lymphoid structures (TLS) are aggregates of T cells, B cells, and dendritic cells that have been shown to predict for response to ICTs in other tumor types but have only rarely been described in prostate cancer.5–10 We sought to evaluate TLS in pre-treatment tumor samples from patients with mCRPC treated with ipilimumab as a predictive biomarker for treatment.Hypothesis TLS in pre-treatment tumor tissues will predict for favorable clinical outcomes to anti-CTLA-4 in patients with mCRPC.Methods Data were analyzed from n=27 patients with mCRPC treated with ipilimumab in a single-center clinical trial ( NCT02113657, MDACC #2013-0444). Patients were stratified into favorable or unfavorable response to ipilimumab based on radiographic progression free survival (rPFS) and overall survival (OS). RNA sequencing data from pre-treatment tumor specimens was downloaded from the European Genome-Phenome Archive (EGAS00001004050) and re-analyzed for quality control. RNA expression analysis (cellular deconvolution, tumor microenvironment reconstruction, and differential gene expression) was performed.11 Pathology review of n=19 H&E slides with available matched data for TLS gene expression was performed to screen for the presence of candidate TLS and lymphoid aggregates [LA].Results ‘Immune-enriched’ tumor microenvironment signatures, including high expression of T cells (including Th1 signatures), mature B cells, and TLS were increased in the group of patients with favorable clinical outcomes. Candidate TLS were observed in 30% of cases (6/20) and LA observed in 15% (3/20). Among patients with ‘immune-enriched’ gene signatures (n=8), TLS or LA were observed in 89% of cases (TLS: 5/8; LA: 2/8). Among patients with ‘non-immune-enriched’ gene signatures (n=11), TLS or LA were observed in 18% (TLS: 1/11; LA: 1/11).Conclusions LA and candidate TLS in pre-treatment tumor tissues were associated with clinical responses to ipilimumab in patients with mCRPC. Concordance was observed between ‘immune-enriched’ gene signatures and presence of LA or candidate TLS. Future studies will focus on protein confirmation of specific cellular subsets comprising TLS and validation of these findings in prospective immune-oncology trials.Trial Registration MDACC 2013-0444 ( NCT02113657) MDACC PA13-0291References Fizazi K, et al. Final analysis of the ipilimumab versus placebo following radiotherapy phase III trial in postdocetaxel metastatic castration-resistant prostate cancer identifies an excess of long-term survivors. Eur Urol. 2020;78:822–830.Beer TM, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. Journal of Clinical Oncology. 2017;35:40–47.Kwon ED, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15: 700–12.Subudhi SK, et al. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci Transl Med. 2020;12:1–11.Cabrita R, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577:561–565.Helmink BA, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577.Petitprez F, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020;577:556–560.Gao J, et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med. 2020;26:1845–1851.Ryan ST, et al. Neoadjuvant rituximab modulates the tumor immune environment in patients with high risk prostate cancer. J Transl Med. 2020;18:214.Shahait M, et al. Quantification and molecular correlates of tertiary lymphoid structures in primary prostate cancer. Prostate. 2024;84:709–716.Zaitsev A, et al. Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes. Cancer Cell. 2022;40:879–894.e16.Ethics Approval This study was approved by the MD Anderson Cancer Center Institutional Review Board under approval numbers: 2013-0444 ( NCT02113657) and PA13-0291.