Background Prostate Cancer (PCa) is a major health concern in developed countries, with rising incidence and progression to advanced stages, necessitating effective treatments. Chronic inflammation is identified as a key factor in PCa pathogenesis and its advancement, creating a complex dynamic between inflammation, genetic changes, and the tumor microenvironment. Under chronic inflammation, the risk of mutation increases due to increased DNA damage and cell regeneration. Inflammation also transforms the tumor microenvironment, promoting tumor growth and potential immune evasion.
Methods Our study used single-stain CD3 IHC, Hyperplex Immunofluorescence (IF), and AI-assisted image analysis to explore the landscape in castration-resistant prostate cancer (CRPC). Evaluating a cohort of 360 hormone-sensitive prostate cancer (HSPC) and 465 CRPC samples, we discovered significant inflammation in a substantial subset, challenging the traditional view of prostate cancer as a ‘cold’ tumor.
Results We leveraged density-based clustering algorithms to decode distinctive spatial patterns of CD3+ cell distribution in CRPC, finding a significant positive correlation with patient survival. We noted diffuse and nodular patterns of CD3+ inflammation, with the nodular pattern associated with worse survival outcomes, possibly indicating immature tertiary lymphoid structures (TLSs). Through IF data, we charted immune landscapes in a smaller CRPC cohort, revealing distinct immune responses in inflamed tumors. We identified high, diffuse inflammation with a prevalence of various immune cells, and another characterized by nodules formation by specific immune cells, hinting at emerging immature TLSs. We observed a correlation between mature TLSs and intense inflammation, suggesting potential NLRP3 inflammasome activation or Senescence Associated Secretory Phenotype (SASP).
Conclusions Our work provides insights into the complex immune microenvironment in CRPC, offering a new understanding of its role in disease progression. The potential biomarkers identified may enhance the effectiveness of immunotherapy, helping to select and monitor patients for immune checkpoint inhibition therapy, with the goal of improving patient outcomes.
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