The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ regulatory T cells (Tregs) in tumors are poorly known. High-dimensional single cell profiling of T cells from chemotherapy-naïve individuals with non-small cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity. In contrast to the IRF4– counterparts, IRF4+ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespectively of the tumor type.
Giorgia Alvisi, Jolanda Brummelman, Simone Puccio, Emilia Maria Cristina Mazza, Elisa Paoluzzi Tomada, Agnese Losurdo, Veronica Zanon, Clelia Peano, Federico S. Colombo, Alice Scarpa, Marco Alloisio, Ajithkumar Vasanthakumar, Rahul Roychoudhuri, Marinos Kallikourdis, Massimiliano Pagani, Egesta Lopci, Pierluigi Novellis, Jonas Blume, Axel Kallies, Giulia Veronesi, Enrico Lugli