Elucidating Prostate Cancer Immunopathology and Immunogenomics Utilizing Computational Analyses of Digital Imaging

Abstract

Prostate Cancer (PCa) is a prominent non-cutaneous malignancy in men in developed countries, necessitating effective treatments. Chronic inflammation is a key factor in PCa pathogenesis and progression, involving a multifaceted interplay between inflammation, genetic aberrations, and the tumour microenvironment. Heightened cellular regeneration due to inflammation-induced DNA damage raises mutation risk, while inflammation fosters angiogenesis and epithelial-mesenchymal transition (EMT), contributing to tumour growth and possible immune evasion.

This study investigated the intricate landscape in castration-resistant prostate cancer (CRPC) using single-stain CD3 Immunohistochemistry (IHC), Hyperplex Immunofluorescence (IF), and AI-assisted image analysis. Screening of 360 hormone-sensitive prostate cancer (HSPC) and 465 CRPC samples revealed considerable inflammation, challenging the perception of PCa as a 'cold' tumour. Notably, distinctive spatial patterns of CD3+ cell distribution across the tumour-stroma interface in CRPC positively correlated with patient survival.

I identified diffuse and nodular patterns of CD3+ inflammation, with nodular inflammation implying worse survival outcomes and potentially indicating immature tertiary lymphoid structures (TLSs) fostering an immunosuppressive environment. Hyperplex IF data from a smaller CRPC cohort highlighted different immune responses in inflamed tumours. Analysis across the tumour-stroma interface identified two immune reaction types: one characterised by high, diffuse inflammation and a variety of immune cells, and the other by B cells, MDSCs, and naïve CD8 cells forming nodules, suggestive of nascent immature TLSs. Mature TLSs correlated with increased inflammation and proliferation of immune cells.

These observations suggest that diffuse inflammation and mature TLSs may indicate NLRP3 inflammasome activation, while immature TLSs might reflect the Senescence Associated Secretory Phenotype (SASP). This enhanced understanding of the CRPC immune microenvironment is pivotal for optimising immunotherapy.

In summary, this study elucidates the complex immune microenvironment in CRPC, proposing an innovative understanding of its role in disease progression and identifying potential biomarkers to enhance treatment efficacy. These insights have implications for patient selection and monitoring in immune checkpoint inhibition therapy, ultimately enhancing patient outcomes in prostate cancer treatment.