{"doi":"10.1101/2020.05.29.123265","title":"Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures","abstract":"Abstract Current immunotherapy paradigms aim to reinvigorate CD8 + T cells, but the contribution of humoral immunity to antitumor immunity remains understudied 1,2 . 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 immunity 5,6 . Novel therapeutics to enhance TIL-B responses in HNSCC should be prioritized as a compliment to current T-cell mediated immunotherapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":122128,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":109265,"name":"Anthony R. Cillo","orcid":"0000-0002-3213-3129","position":1,"is_corresponding":false},{"id":12145,"name":"Tracy Tabib","orcid":"0000-0003-4053-988X","position":2,"is_corresponding":false},{"id":109270,"name":"Angen Liu","orcid":null,"position":3,"is_corresponding":false},{"id":109268,"name":"Sayali Onkar","orcid":"0000-0002-5890-290X","position":4,"is_corresponding":false},{"id":562876,"name":"Sheryl Kunning","orcid":"0000-0001-7529-040X","position":5,"is_corresponding":false},{"id":562877,"name":"Caleb Lampenfeld","orcid":"0000-0002-0613-4494","position":6,"is_corresponding":false},{"id":563863,"name":"Irina Abécassis","orcid":null,"position":7,"is_corresponding":false},{"id":109267,"name":"Zengbiao Qi","orcid":null,"position":8,"is_corresponding":false},{"id":109273,"name":"Ryan J. Soose","orcid":"0000-0001-5200-1505","position":9,"is_corresponding":false},{"id":109271,"name":"Umamaheswar Duvvuri","orcid":"0000-0003-1968-3756","position":10,"is_corresponding":false},{"id":109272,"name":"Seungwon Kim","orcid":"0000-0003-1379-2601","position":11,"is_corresponding":false},{"id":563864,"name":"Steffi Oesterrich","orcid":null,"position":12,"is_corresponding":false},{"id":7274,"name":"Robert Lafyatis","orcid":"0000-0002-9398-5034","position":13,"is_corresponding":false},{"id":109277,"name":"Robert L. Ferris","orcid":"0000-0001-6605-2071","position":14,"is_corresponding":false},{"id":109278,"name":"Dario A.A. Vignali","orcid":"0000-0002-2771-5992","position":15,"is_corresponding":false},{"id":109276,"name":"Tullia C. Bruno","orcid":"0000-0002-6433-0207","position":16,"is_corresponding":false},{"id":562875,"name":"Ayana T. Ruffin","orcid":"0000-0002-5837-5871","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-18T23:14:51.076430Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}