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B cells can regulate immune responses by presenting antigen, producing antigen-specific antibodies and immunomodulatory cytokines. Their role in the anti-tumor immune response is poorly understood. However, in many cancers including head and neck squamous cell carcinoma (HNSCC), intratumoral B cells correlate with better survival. HNSCC has two distinct etiologies (HPV−) and (HPV+) where patients who are HPV+ have increased B cell infiltration and respond better to therapy. We hypothesized that (1) intratumoral B cell phenotype is different between HPV+ and HPV− HNSCC (2) location within the tumor microenvironment (TME) is distinct and (3) antibodies produced by intratumoral B cell in HPV+ HNSCC are specific for viral antigens. Using single-cell RNA sequencing and spectral flow cytometry, we observed that B cell signatures in HPV− HNSCC patients were predominantly memory B cells and plasma cells, while the signatures in HPV+ HNSCC were naïve and germinal center (GC) B cells. Further, we quantified B cells in tertiary lymphoid structures (TLS) using multispectral immunofluorescence, and the presence of GC-rich TLS were increased in HPV+ patients. In fact, GC-rich TLS within the tumor of HPV+ patients correlated with increased overall survival. Overall, high enrichment for GC B cells were positively associated with longer progression-free survival. Antibodies produced by intratumoral B cells from HPV+ patients were positive for HPV viral antigens. Ultimately, characterization of B cell phenotype and function in HNSCC is important for devising new therapeutic options for cancer patients. Specifically, therapeutics to enhance B cell responses in the TME should be prioritized as a compliment to T-cell mediated therapies.

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