Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells

Human regulatory T cells (Tregs) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of Tregs for cancer therapy without affecting immune homeostasis. Identifying pathways that may distinguish tumor-restricted Tregs is important, yet the transcriptional programs that control intratumoral Treg gene expression, and that are distinct from Tregs 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 Tregs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR+ Tregs) that is highly enriched in the tumor microenvironment (TME) compared with nontumor tissue and the periphery. TNFR+ Tregs 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+ Tregs. CRISPR-Cas9–mediated BATF knockout in human activated Tregs 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 Tregs. Last, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral Tregs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral Tregs, highlighting potential opportunities for therapeutic intervention in cancer without affecting immune homeostasis. Description A distinct subpopulation of suppressive intratumoral regulatory T cells correlated with poor prognosis across multiple solid tumors. Editor’s summary Blocking the suppressive activity of CD4+ regulatory T cells (Tregs) to reinvigorate the immune system against tumors comes with substantial risks of adverse effects due to their critical role in immune tolerance. Shan et al. identified a subpopulation of Tregs enriched in the tumor microenvironment specifically by comparing CD4+ T cells from healthy individuals with those from patients with head and neck squamous cell carcinomas. Characterized by gene expression programs and suppressor function under the control of the transcription factor BATF, these distinct Tregs were associated with poorer outcomes across a variety of cancers. Thus, this work indicates that it may be possible to inhibit tumor-infiltrating Tregs by targeting the distinct gene regulatory networks that control their suppressor function without impairing immune homeostasis in general. —Sarah H. Ross

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