The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

Abstract

Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.

Epithelial–Mesenchymal Transition Signaling and Prostate Cancer Stem Cells: Emerging Biomarkers and Opportunities for Precision Therapeutics

“…There is a strong association between reduced expression of E-cadherin and membranous β-catenin and progression in various types of carcinomas, including PCa, which could be used as a prognostic biomarker [21]. Prostate tumors are also able to interact with supporting extracellular matrix and stromal elements to establish a pro-tumorigenic immunosuppressive TME [14,22]. Tumors undergoing EMT may express intermediate morphological, transcriptional, and epigenetic features, that range across the spectrum of epithelial and mesenchymal markers [23].…”

“…Accumulating evidence suggests that some of the common somatic mutations of PCa not only impact classical hallmarks of cancer pathways [ 13 ], but also elicit cellular changes in the tumor microenvironment (TME), allowing cancer cells to avoid immunosurveillance [ 14 ]. One of the molecular processes associated with aggressive cancers that is also known to impact the TME is EMT [ 15 ].…”

“…There is a strong association between reduced expression of E-cadherin and membranous β-catenin and progression in various types of carcinomas, including PCa, which could be used as a prognostic biomarker [ 21 ]. Prostate tumors are also able to interact with supporting extracellular matrix and stromal elements to establish a pro-tumorigenic immunosuppressive TME [ 14 , 22 ].…”

“…Prostate tumors interact closely with the TME and stromal elements adjacent to tumor cells, which creates an immunosuppressive TME [ 14 , 22 ]. An early study on this topic highlights the role of cancer-associated fibroblast (CAFs) in the TME of PCa.…”

Personalized 1-2-3-Gene(s) Tickets to Cancer-Free Prostate

“…Problem is that recent evidence indicates that most cancerous prostates harbor genetically distinct, independently developing malign clones [10]. This tumor heterogeneity [11,12], both at histo-pathological and transcriptomic [13,14] levels within the prostate of one patient as well as among patients, complicates significantly the treatment options [15][16][17]. Moreover, together with the biomarker(s) whose altered sequence or expression level is thought indicative for that cancer type, unique combinations of hundreds other genes are mutated or/and regulated in each cancer nodule with respect to the surrounding, cancer-free tissue [18].…”