Abstract 1175: Differential patterns of immune infiltration in the tumor immune microenvironment associate with therapeutic response in primary prostate cancer following chemohormonal therapy
Authors: Heninger Erika , Sperger Jamie M. , Weinstein Kristin , Johnson Brian P. , Geiger Peter G. , Wells Shane , Cho Steve Y. , Huang Wei , Tsourkas Philippos , McIlwain Sean , Ong Irene M. , Kerr Sheena C. , Jarrard David F. , Beebe David J. , Lang Joshua M. 
Published: March 2024

Abstract
There is a critical need to develop novel therapeutic strategies and diagnostic tools to precisely deliver treatments to improve survival for men with prostate cancer. To support this development, improved strategies are needed to better understand heterogenous tumor microenvironments and tumor biology that associate with variable treatment responses. We hypothesized that the tumor immune microenvironment (TIME) plays a critical role in treatment resistance. In this study we aimed to evaluate TIME signatures of treatment response and resistance utilizing a novel, integrated technological tool to identify response patterns and enable precision sampling for comparative cellular and molecular analysis.
30 patients with newly diagnosed, locally advanced, high-risk, primary prostate cancer underwent 18F-DCFPyL PSMA PET/MRI with multiparametric MRI scans followed by 3 cycles of chemohormonal therapy (NCT03358563). Repeat PSMA PET/MRI was performed prior to prostatectomy and scans were used to categorize lesions as complete response (CR), partial response (PR), no response (NR) or normal tissue. MRI scans were used to print a 3D mold of the prostate to allow microdissection of regions of interest from the resected prostate. Cellular infiltrates were analyzed by flow cytometry in 3 to 5 tissue specimens per patient. Statistical analysis was performed with One-way ANOVA with Tukey-correction.
The frequency of CD8+ T cells in the total CD45+ infiltrate was highest in normal and CR areas and was significantly reduced in PR vs CR (p&lt;0.01). CXCR3+CD8+ and CD103+CD8+ T cell frequencies were also reduced in PR vs CR foci (p&lt;0.01, p&lt;0.05, respectively). Meanwhile, the frequency of CXCR3+CD8+ T cells was highest and significantly elevated in CR vs normal tissue. A tendency of reduced CCR6+, CXCR5+, and CCR4+CD8+ T cells was observed in PR vs CR foci, while those frequencies remained higher in normal and CR areas. An increase in total CD8+ and CD103+CD8+ T cells associated with longer progression-free survival. Additionally, the analysis of EpCAM+ cells showed a significant increase in B7H3 expression in PR vs CR lesions (p&lt;0.05) and a tendency of reduced HLA I expression in foci that associated with treatment resistance. We are currently integrating analysis of myeloid cells and transcriptomic analysis of sorted CD4+, CD8+ and CD11b/CD14+ cells to further dissect patterns of therapeutic response in our study cohort.
In conclusion, PSMA/PET MRI based precision sampling of tumor tissue associated with differential therapeutic response patterns captured differences in the TIME infiltrates and these observations may provide hypothesis to test biological mechanisms to expedite discovery of targetable mechanisms to improve tumor stratification and targeting in high-risk prostate cancer.
Citation Format: Erika Heninger, Jamie M. Sperger, Kristin Weinstein, Brian P. Johnson, Peter G. Geiger, Shane Wells, Steve Y. Cho, Wei Huang, Philippos Tsourkas, Sean McIlwain, Irene M. Ong, Sheena C. Kerr, David F. Jarrard, David J. Beebe, Joshua M. Lang. Differential patterns of immune infiltration in the tumor immune microenvironment associate with therapeutic response in primary prostate cancer following chemohormonal therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1175.