A B cell-IgA-epithelial axis enhances antitumor immunity and improves outcome in HPV-associated penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) is a rare, aggressive malignancy, with HPV driving approximately 50% of cases and correlating with improved outcomes. In this study, we perform single-cell RNA sequencing on tumor microenvironment (TME) cells from 23 treatment-naive PSCC patients, including 11 cases reported previously, and validate our findings in a larger cohort of 85 patients. Our analysis reveals significant immune cell infiltration in PSCC, with HPV+ tumors exhibiting elevated levels of tumor-infiltrating B cells, plasma cells, tertiary lymphoid structures, and IgA secretion. A subset of malignant epithelial cells in HPV+ PSCC express the polymeric IgA receptor (PIGR), facilitating IgA transcytosis and inducing anti-tumor responses. Functional studies show that PIGR overexpression promotes tumor apoptosis and enhances immune responses, with these effects diminish in IgA-deficient mice. Elevated IgA and PIGR expression correlate with improved survival. These findings provide a single-cell atlas of the PSCC TME, highlighting the B cell-IgA-PIGR axis as a pivotal driver of antitumor immunity and clinical outcomes in HPV+ PSCC.