GC TIL-Bs in HPV + HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone, and transitional state of GC B cells. SEMA4A expression is increased on GC TIL-Bs compared to other TIL-B subsets and is associated with TIL-B differentiation and TLS containing GCs in HNSCC. GC TIL-Bs and TLS with GC are increased in HPV + HNSCC patients and correlate with better outcomes. Here, we demonstrate that TIL-Bs in HPV + and HPV − HNSCC have distinct transcriptional signatures. Understanding the features that drive TIL-Bs toward a GC phenotype and contribute to the development and maintenance of GCs within TLS in the TME would provide a path to enhancing antitumor immunity in patients. ![]() In support of this, GC-like TIL-Bs were found to be increased in melanoma patients who responded to ICB 6. Ultimately, GCs within TLS in the TME are indicative of maximal engagement of the humoral arm of the immune system in antitumor immune responses. However, SEMA4A expression on GC TIL-B has not been previously reported in human cancer. In addition, recent studies have indicated Semaphorin 4A (SEMA4A) expression on human GC B cells in SLOs 27. GC B cells can be further divided into centroblasts (dark zone DZ) and centrocytes (light zone LZ) through the expression of CXCR4 and CD86, respectively. In humans, GC B cells are commonly identified as CD38 + IgD − and transcription factor BCL6 +. GCs are typically found in SLOs and are responsible for producing affinity matured and class switched B cells that effectively recognize their cognate antigen, leading to memory B cells and durable humoral immunity. One feature associated with mature TLS is the formation and presence of germinal centers (GCs) 26. Additionally, understanding the factors that drive the formation of TLS would permit the identification of therapeutic avenues to foster an influx of antitumor TIL-Bs into the TME. Characterization of TLS in the TME, including their composition, spatial organization, and maturity would provide critical insight into the roles these structures play in antitumor immunity. However, TLSs are quite heterogeneous structures 25, and the composition of TIL-Bs within these structures has not been fully elucidated. Recent studies have demonstrated that the presence of B cells and TLS in melanoma, renal cell carcinoma, sarcoma, and HNSCC are associated with better responses to immune checkpoint blockade (ICB) 6, 7, 23, 24. TLSs have been shown to also correlate with increased patient survival in many human tumors 21, 22. TLS are characterized by organization patterns similar to SLOs with defined T cell zones, B cell rich follicles and mature dendritic cells (DCs) 19, 20. Tertiary lymphoid structures (TLSs) are immune aggregates with varying degrees of organization that form outside of secondary lymphoid organs (SLOs) in response to chronic inflammation or infection 17, 18. Understanding B cell phenotypes and the spatial organization of immune populations in the TME of patients in both viral and carcinogen-induced cancers will provide critical insight into how TIL-Bs can be leveraged to enhance antitumor immunity. While the mechanisms underlying this difference in outcomes remains unknown, TIL-B are more frequent in HPV + versus HPV – HNSCC 5, 15, 16. ![]() Patients with HPV + HNSCC have historically had better outcomes compared to HPV – patients 13, 14. HNSCC offers a unique avenue to study TIL-Bs in the tumor microenvironment (TME) as HNSCC cancer can be caused by both exposure to environmental carcinogens or infection with high-risk human papillomavirus (HPV) 12. Specifically, increased TIL-Bs have been reported in cancers caused by environmental exposure to carcinogens (i.e., tobacco, alcohol, UV exposure) such as lung cancer and melanoma as well as cancers caused by viral infection such as hepatocellular carcinoma (HCC) and Merkel cell carcinoma (MCC) 6, 8, 9, 10, 11. Tumor infiltrating B cells (TIL-Bs) represent a possible new target to compliment T cell-based immunotherapies, as they are frequent in many human tumors and positively correlate with favorable patient outcomes 4, 5, 6, 7. Immunotherapies targeting the programmed cell death protein 1 (PD1) pathway are approved by the Food and Drug Administration for the treatment of several metastatic or unresectable cancers including head and neck squamous cell carcinoma (HNSCC), but only ~20% of patients achieve a clinical benefit, highlighting the need for new therapeutic targets 1, 2, 3.
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