26Current immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution 27 of humoral immunity to antitumor immunity remains understudied1,2. Head and neck 28 squamous cell carcinoma (HNSCC) is caused by either human papillomavirus (HPV+) or 29 environmental carcinogens (i.e. tobacco and alcohol; HPV-)3,4. Here, we demonstrate that 30 HPV+ HNSCC patients have transcriptional signatures of germinal center (GC) tumor 31 infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with GC-32 like tertiary lymphoid structures (TLS), both of which correlate with favorable outcomes in 33 HNSCC patients. Further, our single-cell RNAseq data also indicate that GC TIL-Bs are 34 characterized by distinct waves of gene expression consistent with dark zone, light zone 35 and a transitional state of GC B cells. High-dimensional spectral flow cytometry permitted 36 in depth characterization of activated, memory and GC TIL-Bs. Further, single cell RNAseq 37 analysis and subsequent protein validation identified a role for semaphorin 4a (Sema4a) 38 in the differentiation of GC TIL-Bs and indicated that expression of Sema4a was enhanced 39 on GC TIL-Bs and within GC-like TLS in the TME. Thus, in contrast to some reports on the 40 detrimental role of TIL-Bs in human tumors, our findings suggest that TIL-Bs play an 41 instrumental role in antitumor immunity5,6. Novel therapeutics to enhance TIL-B responses 42 in HNSCC should be prioritized as a compliment to current T-cell mediated 43 immunotherapies. 65 organization that form outside of secondary lymphoid organs (SLOs) in response to chronic 66 inflammation or infection20,21. TLS are characterized by organization patterns similar to SLOs with 67 defined T cell zones, B cell rich follicles and mature dendritic cells (DCs)22,23. TLS have been 68 shown to also correlate with increased patient survival in many human tumors24,25. Recent studies 69 have demonstrated that the presence of B cells and TLS in melanoma, renal cell carcinoma, 70 sarcoma, and HNSCC are associated with better responses to immune checkpoint blockade 71 Ruffin et al. Cancer etiologies drive B cells and TLS 4 (ICB)10,11,26,27. However, TLS are quite heterogeneous structures28, and the composition of TIL-Bs 72 within these structures has not been fully elucidated. Characterization of TLS in the TME, 73 including their composition, spatial organization, maturity, and phenotypes of immune cells 74 involved would provide critical insight into the roles these structures play in antitumor immunity. 75 Additionally, understanding the factors that drive formation of TLS within the TME would permit 76 the identification of therapeutic avenues to foster an influx of TIL-Bs into the proper spatial 77 organization. 78 One feature associated with mature TLS is the formation and presence of germinal centers 79 (GCs)29. GCs are typically found in SLOs and are responsible for producing affinity matured and 80 class switched B cells that effectively recognize their cognate antigen, leading to m...
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