Sledzinska et al. showed that tumor-reactive CD4+ T cells transferred into anti-CTLA-4-treated irradiated mice rejected established tumors. Tumor-infiltrating CD4+ T cells (TILs), capable of tumor cell killing in vitro, coexpressed Tbet (required for IFNγ expression) and Blimp-1 (for TNFα and IL-2-induced granzyme B). Tumor control was reduced in IFNγR-/- mice or by Blimp-1 or perforin deficiency in transferred CD4+ T cells. Treg depletion boosted IL-2 to induce TIL granzyme B expression. Patients with advanced melanoma who had been treated with anti-CTLA-4 and melphalan had an inverse association of TIL Treg frequency and granzyme B expression.
Contributed by Paula Hochman
In addition to helper and regulatory potential, CD4(+) T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4(+) T cells following immunotherapy. CD4(+) transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4(+), and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-gamma (IFN-gamma) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4(+) T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4(+) T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation.
Author Info: (1) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, L
Author Info: (1) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. (2) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Regulatory Genomics Research Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK. (3) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. (4) Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. (5) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. (6) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. (7) Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. (8) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. (9) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. (10) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. (11) Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. (12) Faculty of Natural Sciences, Department of Life Sciences, Imperial College London, London SW7 2BB, UK. (13) Institute of Immunity and Transplantation, Department of Immunology, Royal Free Hospital, London NW3 2PF, UK. (14) Retroviral Immunology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (15) Memorial Sloan Kettering Center, 1275 York Avenue, New York, NY 10065, USA. (16) Department of Experimental Neuroimmunology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany. (17) Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. (18) Faculty of Biology, Medicine and Health, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK. (19) Institute of Immunity and Transplantation, Department of Immunology, Royal Free Hospital, London NW3 2PF, UK. (20) Regulatory Genomics Research Group, UCL Cancer Institute, University College London, London WC1E 6DD, UK. (21) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. Electronic address: k.peggs@ucl.ac.uk. (22) Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. Electronic address: s.quezada@ucl.ac.uk.
