Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures
Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures
Abstract Current immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied1,2. Head and neck squamous cell carcinoma (HNSCC) is caused by either human papillomavirus (HPV+) or environmental carcinogens (i.e. tobacco and alcohol; HPV–)3,4. Here, we demonstrate that HPV+ HNSCC patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with GC-like tertiary lymphoid structures (TLS), both of which correlate with favorable outcomes in HNSCC patients. Further, our single-cell RNAseq data also indicate that GC TIL-Bs are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. High-dimensional spectral flow cytometry permitted in depth characterization of activated, memory and GC TIL-Bs. Further, single cell RNAseq analysis and subsequent protein validation identified a role for semaphorin 4a (Sema4a) in the differentiation of GC TIL-Bs and indicated that expression of Sema4a was enhanced on GC TIL-Bs and within GC-like TLS in the TME. Thus, in contrast to some reports on the detrimental role of TIL-Bs in human tumors, our findings suggest that TIL-Bs play an instrumental role in antitumor immunity5,6. Novel therapeutics to enhance TIL-B responses in HNSCC should be prioritized as a compliment to current T-cell mediated immunotherapies.
Lafyatis Robert、Vignali Dario AA、Bruno Tullia C、Liu Angen、Qi Zengbiao、Soose Ryan、Oesterrich Steffi、Cillo Anthony R、Tabib Tracy、Onkar Sayali、Ruffin Ayana T、Lampenfeld Caleb、Duvvuri Umamaheswar、Abecassis Irina、Kunning Sheryl、Kim Seungwon、Ferris Robert L
Department of Medicine, University of PittsburghDepartment of Immunology, University of Pittsburgh||Tumor Microenvironment Center, Hillman Cancer Center, University of Pittsburgh||Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer CenterDepartment of Immunology, University of Pittsburgh||Tumor Microenvironment Center, Hillman Cancer Center, University of Pittsburgh||Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer CenterDepartment of Otolaryngology, University of PittsburghDepartment of Medicine, University of PittsburghDepartment of Otolaryngology, University of PittsburghDepartment of Pharmacology and Chemical Biology, University of Pittsburgh||Women?ˉs Cancer Research Center, Magee-Womens Research Institute, University of PittsburghDepartment of Immunology, University of Pittsburgh||Tumor Microenvironment Center, Hillman Cancer Center, University of PittsburghDepartment of Medicine, University of PittsburghDepartment of Immunology, University of Pittsburgh||Tumor Microenvironment Center, Hillman Cancer Center, University of Pittsburgh||Program in Microbiology and Immunology, University of Pittsburgh School of MedicineDepartment of Immunology, University of Pittsburgh||Tumor Microenvironment Center, Hillman Cancer Center, University of Pittsburgh||Program in Microbiology and Immunology, University of Pittsburgh School of MedicineDepartment of Immunology, University of Pittsburgh||Tumor Microenvironment Center, Hillman Cancer Center, University of PittsburghDepartment of Otolaryngology, University of PittsburghDepartment of Immunology, University of Pittsburgh||Tumor Microenvironment Center, Hillman Cancer Center, University of PittsburghDepartment of Immunology, University of Pittsburgh||Tumor Microenvironment Center, Hillman Cancer Center, University of PittsburghDepartment of Otolaryngology, University of PittsburghDepartment of Immunology, University of Pittsburgh||Tumor Microenvironment Center, Hillman Cancer Center, University of Pittsburgh||Department of Otolaryngology, University of Pittsburgh||Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center
肿瘤学基础医学
Lafyatis Robert,Vignali Dario AA,Bruno Tullia C,Liu Angen,Qi Zengbiao,Soose Ryan,Oesterrich Steffi,Cillo Anthony R,Tabib Tracy,Onkar Sayali,Ruffin Ayana T,Lampenfeld Caleb,Duvvuri Umamaheswar,Abecassis Irina,Kunning Sheryl,Kim Seungwon,Ferris Robert L.Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures[EB/OL].(2025-03-28)[2025-05-19].https://www.biorxiv.org/content/10.1101/2020.05.29.123265.点此复制
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