Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells

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.

Interleukin-17 directly stimulates tumor infiltrating Tregs to prevent cancer development

“…Pancreatic cancer data ( 32 ) was obtained from the GEO accession number GSE155698. Melanoma data ( 33 ) was obtained from GSE239750. Triple-negative breast cancer data ( 34 ) was obtained from GSE169246.…”

Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review

“…Their existence is linked to a negative outlook for HNSCC patients. A transcriptional circuit, centered on the basic leucine zipper ATF-like transcription factor (BATF), was inferred by constructing a regulatory network for scRNA-seq.BATF is a crucial element that controls the transcription and activity of TNFR + Tregs in the TME [ 32 ]. Various subpopulations of Tregs with varied phenotypes and functions are present in TME, but the amount of distinctions between these subtypes is not fully understood.…”