Exploring the Potential Value of tumor Immunological Phenotype-Related Gene Signature in Predicting Prognosis and Immunotherapy Efficacy of Prostate Cancer Among Physically Active and Athletic Individuals

Abstract

Background: Prostate cancer is a predominant cause of cancer-related deaths among men worldwide, with varying responses to immunotherapy, especially in physically active and athletic individuals. This demographic may experience different disease progression and treatment outcomes due to their unique physiological and lifestyle factors. This study introduces a novel prognostic tool, the Tumor Immunological Phenotype-Related Gene Prognostic Index (TIPRGPI), derived from the tumor immune microenvironment (TIME), aimed at improving predictions of survival outcomes and responses to immunotherapy specifically in prostate cancer patients who are physically active or engaged in regular athletic activities. Methods: Our approach began with the identification of a tumor immunological phenotype (TIP) gene signature from the literature. Using weighted gene co-expression network analysis (WGCNA), we pinpointed a TIP-associated gene module. From this, we selected pivotal genes to construct the TIPRGPI through Cox proportional hazards modeling and LASSO regression. We compared survival outcomes across different TIPRGPI strata using Kaplan-Meier analysis and developed a nomogram for visualizing survival risks. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were utilized to identify distinct hallmark pathways across TIPRGPI categories. Mutation profiles were explored through genetic variation analysis, and the degree of immune cell infiltration within TIME was quantified using single-sample GSEA (ssGSEA), with a particular focus on how these factors might differ in athletic individuals. Results: The establishment of TIPRGPI was based on 12 critical genes. Athletically active patients within the high-score TIPRGPI group showed a significantly increased mortality risk compared to those in the low-score group. There were significant differences in hallmark pathways and mutation profiles associated with TIPRGPI scores, as well as a notable correlation between TIPRGPI scores and immune cell infiltration levels in TIME, suggesting unique prognostic factors in physically active prostate cancer patients. Conclusions: The TIPRGPI emerges as a significant prognostic tool for assessing survival and the potential success of immunotherapy in prostate cancer patients, with an enhanced focus on those who are physically active or athletic. The genes, pathways, and immune cells identified in relation to TIPRGPI scores highlight promising directions for targeted therapies and personalized treatment approaches. This tailored approach underscores the need for considering physical activity levels and lifestyle in managing prostate cancer, aiming to optimize treatment efficacy and improve outcomes for this specific patient subgroup.