Whiteside et al. investigated mechanisms underlying the limited clinical success of Treg cell-depleting therapies. Using a mouse model of Treg-targeted immunotherapy, depletion of Foxp3+ Tregs drove expansion and conversion of CD4+Foxp3- conventional T (Tconv) cells within tumors to acquire a Treg-like transcriptional profile with suppressive activity ex vivo. Treg ablation resulted in activation and expansion of CCR8+ Tconv cells that suppressed tumor immunity via IL-10 production. Inhibition of IL-10 by conditional deletion of T cell Il10 or by Ab blockade of IL-10 signaling was synergistic with Treg depletion, and prevented treatment resistance.
Contributed by Katherine Turner
ABSTRACT: Regulatory T (T(reg)) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt T(reg) cell-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling T(reg) cell-targeted immunotherapy in mice, we find that CD4(+) Foxp3(-) conventional T (T(conv)) cells acquire suppressive function upon depletion of Foxp3(+) T(reg) cells, limiting therapeutic efficacy. Foxp3(-) T(conv) cells within tumors adopt a T(reg) cell-like transcriptional profile upon ablation of T(reg) cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4(+) T(conv) cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon T(reg) cell depletion, CCR8(+) T(conv) cells undergo systemic and intratumoral activation and expansion, and mediate IL-10-dependent suppression of antitumor immunity. Consequently, conditional deletion of Il10 within T cells augments antitumor immunity upon T(reg) cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with T(reg) cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by T(conv) cells released upon therapeutic T(reg) cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective T(reg) cell-targeted therapies.
Author Info: (1) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (2) Immunology Programme, Babraham Institute, Babraham Research Campus, Cambridge,
Author Info: (1) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (2) Immunology Programme, Babraham Institute, Babraham Research Campus, Cambridge, Cambridgeshire CB22 3AT, UK. (3) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy. (4) La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA. (5) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (6) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (7) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (8) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (9) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (10) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (11) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (12) Division of Infection and Immunity/System Immunity University Research Institute, Cardiff University, Cardiff CF14 4XN, UK. (13) Division of Infection and Immunity/System Immunity University Research Institute, Cardiff University, Cardiff CF14 4XN, UK. (14) Division of Infection and Immunity/System Immunity University Research Institute, Cardiff University, Cardiff CF14 4XN, UK. (15) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (16) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (17) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (18) Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy. Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy. (19) Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy. Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy. (20) Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (21) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK. (22) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy. (23) Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
