Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity

• Published in: The Journal of clinical investigation 2021-10, Vol.131 (19), p.1-17
• Main Authors: Noël, Grégory, Fontsa, Mireille Langouo, Garaud, Soizic, De Silva, Pushpamali, de Wind, Alexandre, Van den Eynden, Gert G, Salgado, Roberto, Boisson, Anaïs, Locy, Hanne, Thomas, Noémie, Solinas, Cinzia, Migliori, Edoardo, Naveaux, Céline, Duvillier, Hugues, Lucas, Sophie, Craciun, Ligia, Thielemans, Kris, Larsimont, Denis, Willard-Gallo, Karen
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Biomedical research; Breast cancer; Breast Neoplasms - immunology; Care and treatment; CD25 antigen; CD4 antigen; CD4 lymphocytes; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Clinical outcomes; CXCL13 protein; CXCR5 protein; Cytotoxicity; Female; Flow cytometry; Foxp3 protein; Gene expression; Genotype & phenotype; Germinal centers; Health aspects; Helper cells; Humans; Immune response; Immune system; Immunoglobulins; Immunological memory; Immunotherapy; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Membrane Proteins - analysis; Membrane Proteins - physiology; PD-1 protein; PD-L1 protein; Phenotypes; Physiological aspects; Programmed Cell Death 1 Receptor - analysis; Receptors, CXCR5 - analysis; T Follicular Helper Cells - immunology; T-Lymphocytes, Regulatory - immunology; Th1 Cells - immunology; Tumor-infiltrating lymphocytes; Tumors; γ-Interferon
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI139905

We previously demonstrated that tumor-infiltrating lymphocytes (TIL) in human breast cancer sometimes form organized tertiary lymphoid structures (TLS) characterized by CXCL13-producing T follicular helper (Tfh) cells. The present study found that CD4+ Tfh TIL, CD8+ TIL, and TIL-B, colocalizing in TLS, all express the CXCL13 receptor CXCR5. An ex vivo functional assay determined that only activated, functional Th1-oriented Tfh TIL (PD-1hiICOSint phenotype) provide help for immunoglobulin and IFN-γ production. A functional Tfh TIL presence signals an active TLS, characterized by humoral (immunoglobulins, Ki-67+ TIL-B in active germinal centers) and cytotoxic (GZMB+CD8+ and GZMB+CD68+ TIL plus Th1 gene expression) immune responses. Analysis of active versus inactive TLS in untreated patients revealed that the former are associated with positive clinical outcomes. TLS also contain functional T follicular regulatory (Tfr) TIL, which are characterized by a CD25+CXCR5+GARP+FOXP3+ phenotype and a demethylated FOXP3 gene. Functional Tfr inhibited functional Tfh activities via a glycoprotein A repetitions predominant (GARP)-associated TGF-β-dependent mechanism. The activity of tumor-associated TLS was dictated by the relative balance between functional Tfh TIL and functional Tfr TIL. These data provide mechanistic insight into TLS processes orchestrated by functional Th1-oriented Tfh TIL, including TIL-B and CD8+ TIL activation and immunological memory generation. Tfh TIL, regulated by functional Tfr TIL, are an expected key target of PD-1/PD-L1 blockade.