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Characterization of the genetic mechanisms leading to immune evasion in the tumor microenvironment of prostate cancer

Grant number: 19/22912-8
Support type:Regular Research Grants
Duration: May 01, 2020 - April 30, 2022
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Jeremy Andrew Squire
Grantee:Jeremy Andrew Squire
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers: Fabiano Pinto Saggioro ; Luciano Neder Serafini ; Rodolfo Borges dos Reis ; Sergio Akira Uyemura ; Tamara L Lotan ; Thiago Vidotto

Abstract

Immunotherapy has improved patient survival in many types of cancer, but in prostate cancer (PCa) initial results with immunotherapy have been disappointing. This tumor is considered immunologically "cold" and unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients with PCa do respond to immunotherapy for reasons that are presently unknown. These data suggest that patient selection based on biomarkers that predict an effective immune response might be instrumental in delivering success with immunotherapy in PCa. Our data and recent findings from the literature suggests that somatic mutations affecting the PTEN, TP53, CDK12, and ETS fusions could change gene expression to help PCa avoid immunosurveillance. Our overall hypothesis is that PCa that fail to respond to checkpoint inhibitors have acquired specific somatic mutations that lead to transcriptional changes in the tumor that influence the immune cells and secreted cytokines in the tumor microenvironment, facilitating immune evasion. In our experimental design, we will determine the impact of these four mutational PCa subtypes on cellular changes affecting tumor-infiltrating immune cells and other cell types in the tissue microenvironment of PCa as determined by flow cytometry. Our cytometric analysis will identify the immune cell types such as Myeloid Derived Suppressor Cells (MDSCs), Regulatory T-cells (Tregs), Cancer Associated Fibroblasts (CAFs), Tumor Associated Macrophages (TAMs) and dendritic cells that are associated with tumor immunosuppression. We will confirm the identity of cell types and tumor-immune cell interactions by immunofluorescence microscopy. We will also analyze cytokine levels associated with immune response. Then, we will perform transcriptional analysis of an immune response panel of 395 genes comparing representative tumors with cellular and mutational features strongly associated with an immune evasion to a representative tumor group with fewer features of immune evasion. This analysis will provide novel expression information on immune pathways already linked to immune evasion in the literature that may act downstream of the mutational subtypes. We will correlate expression changes in specific immune response pathways with the presence of ETS fusions and mutations of PTEN, TP53, CDK12 in the context of changing immune cell content, variation in T-cell activation states, and activation of cytokine signaling in the tumor microenvironment. Expression changes in the most informative genes will be validated by quantitative RT-PCR using the entire cohort from this study. We will validate cellular findings in the tissue microenvironment of our cohort of 91 PCa developed as part of our previously funded FAPESP study and through collaborative studies with Johns Hopkins. Our analysis will allow us to identify a panel of 20-30 genes for use as predictive biomarkers of activation of immune evasion in the TME of PCa. We believe that understanding how the common somatic mutations in PCa can lead to transcriptional changes affecting immune response will provide new approaches for improving success with immunotherapy in this tumor. (AU)