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Introduction Adaptive and innate antitumor immune responses and their exploitation in immunotherapy are recognized as key defenses in the fight against cancer. Across a diversity of tumor types, data support [...], 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.sup.+] Tfh TIL, [CD8.sup.+] TIL, and TIL-B, colocalizing in TLS, all express the CXCL13 receptor CXCR5. An ex vivo functional assay determined that only activated, functional Thl-oriented Tfh TIL ([PD-1.sup.hi][ICOS.sup.int] phenotype) provide help for immunoglobulin and IFN-[gamma] production. A functional Tfh TIL presence signals an active TLS, characterized by humoral (immunoglobulins, [Ki-67.sup.+] TIL-B in active germinal centers) and cytotoxic ([GZMB.sup.+][CD8.sup.+] and [GZMB.sup.+][CD68.sup.+] 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.sup.+][CXCR5.sup.+][GARP.sup.+][FOXP3.sup.+] phenotype and a demethylated FOXP3 gene. Functional Tfr inhibited functional Tfh activities via a glycoprotein A repetitions predominant (GARP)-associated TGF-[beta]-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.sup.+] TIL activation and immunological memory generation. Tfh TIL, regulated by functional Tfr TIL, are an expected key target of PD-1/PD-L1 blockade.

[CD4.sup.+] T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image [...]