Immunosuppressive role of benzo[a]pyrene exposure in prostate cancer progression

Abstract

Epidemiological studies indicate that prostate cancer (PCa) is the second prevalent malignant tumor affecting men globally. Environmental pollution such as cigarette smoke is one of the important risk factors for the development of prostate cancer. However, as one of the main carcinogens in cigarette smoke, the role of benzo[a]pyrene (BaP) in prostate cancer is still unclear. The current study aimed to investgate the impacts of BaP exposure on the progression of PCa toward malignancy and the regulation of the immune microenvironment. We verified that BaP exposure can promote the proliferation, migration, and apoptosis of prostate cancer cells through in vitro experiments. We constructed a subcutaneous xenograft tumor model of BaP exposure mouse and found that can promote the proliferation of tumors in vivo. Organoids-driven by PCa patients showed higher growth rate under BaP exposure. Flow cytometric analysis demonstrated a remarkable decrease in CD4⁺ T and CD8⁺ T cell infiltration levels. Moreover, we identified four genes (Mdm2, Ar, Foxo1, Crebbp) were strongly associated with BaP exposure by combining mouse tumor RNA-seq and CTD database. Additionally, a nomogram integrating clinicopathological features was constructed to assess the prognosis of prostate cancer patients under BaP exposure. This study systematically proved that BaP exposure promotes malignant progression of PCa and suppresses the immune microenvironment, in which Mdm2, Ar, Foxo1, Crebbp may play a crucial role in inhibiting apoptosis. These findings offer novel insights into the mechanisms via which BaP exposure contributes to PCa development.