Shan et al. determined specific characteristics of tumor-infiltrating Tregs (TIL Tregs) in head and neck squamous cell carcinoma (HNSCC), as compared to peripheral Tregs. TIL Tregs expressed activation and suppressive phenotypic markers, including coinhibitory receptors and several TNFR superfamily members (TNFR+ Tregs). TNFR+ Tregs were found in multiple cancer types and were associated with worse prognosis. Several transcription factors were enriched in these Tregs, including BATF, which was predicted to regulate key signatures of TIL Tregs. BATF KO in Tregs suggested BATF affects Treg tumor infiltration, activation, phenotype, and survival.
Contributed by Maartje Wouters
ABSTRACT: Human regulatory T cells (T(regs)) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of T(regs) for cancer therapy without affecting immune homeostasis. Identifying pathways that may distinguish tumor-restricted T(regs) is important, yet the transcriptional programs that control intratumoral T(reg) gene expression, and that are distinct from T(regs) in healthy tissues, remain largely unknown. We profiled single-cell transcriptomes of CD4(+) T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC) and those in nontumor tonsil tissues and peripheral blood from healthy donors. We identified a subpopulation of activated T(regs) expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR(+) T(regs)) that is highly enriched in the tumor microenvironment (TME) compared with nontumor tissue and the periphery. TNFR(+) T(regs) are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR(+) T(regs). CRISPR-Cas9-mediated BATF knockout in human activated T(regs) in conjunction with bulk RNA sequencing, immunophenotyping, and in vitro functional assays corroborated the central role of BATF in limiting excessive activation and promoting the survival of human activated T(regs). Last, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral T(regs) in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral T(regs), highlighting potential opportunities for therapeutic intervention in cancer without affecting immune homeostasis.
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Integrative Systems Biology Program, University of Pittsburgh School of Medicine, Pi
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Integrative Systems Biology Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (2) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (3) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (4) Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (5) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (6) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (7) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (8) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (9) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (10) Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (11) Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (12) Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (13) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (14) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (15) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (16) Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Department of Epidemiology, University of Florida, Gainesville, FL, USA. (17) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
