Guillerey and Harjunpaa et al. show that TIGIT is the dominant immune checkpoint in multiple myeloma (MM) in both mice and humans, and that the percentage of TIGIT+CD8+ T cells correlate with MM burden in mice. In human MM, TIGIT+CD8+ T cells are exhausted and have impaired cytokine production, proliferation, and cytotoxicity. Blockade of the TIGIT pathway in vivo in mice, either via knockout or antibody, reduced tumor burden and improved survival in a CD8+ T cell-dependent manner, and anti-TIGIT antibody also increased CD8+ T cell effector function.
Immune-based therapies hold promise for the treatment of multiple myeloma (MM), but so far immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) has not proven effective as single agent in this disease. T cell immunoglobulin and ITIM domains (TIGIT) is another immune checkpoint receptor known to negatively regulate T cell functions. In this study, we investigated the therapeutic potential of TIGIT blockade to unleash immune responses against MM. We observed that, in both mice and humans, MM progression was associated with high levels of TIGIT expression on CD8(+) T cells. TIGIT(+) CD8(+) T cells from MM patients exhibited a dysfunctional phenotype, characterized by decreased proliferation and inability to produce cytokines in response to anti-CD3/CD28/CD2 or myeloma antigen stimulation. Moreover, when challenged with Vk*MYC mouse MM cells, TIGIT-deficient mice showed decreased serum M-protein levels associated with reduced tumor burden and prolonged survival, indicating that TIGIT limits anti-myeloma immune responses. Importantly, blocking TIGIT using monoclonal antibodies (mAbs) increased the effector function of MM patient CD8(+) T cells and suppressed MM development. Altogether our data provide evidence for an immune-inhibitory role of TIGIT in MM and support the development of TIGIT-blocking strategies for the treatment of MM patients.
Author Info: (1) Immunology in Cancer and Infection Laboratory, School of Medicine, QIMR Berghofer Medical Research Institute, The University of Queensland, Herston, Australia. (2) School of Me
Author Info: (1) Immunology in Cancer and Infection Laboratory, School of Medicine, QIMR Berghofer Medical Research Institute, The University of Queensland, Herston, Australia. (2) School of Medicine, Cancer Immunoregulation and Immunotherapy Laboratory, The University of Queensland, QIMR Berghofer Medical Research Institute, Herston, Australia. (3) Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France. (4) Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France. (5) Immunology in Cancer and Infection Laboratory, School of Medicine, QIMR Berghofer Medical Research Institute, The University of Queensland, Herston, Australia. (6) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. (7) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. (8) Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France. (9) Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France. (10) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. (11) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. (12) Bone Marrow Transplantation Cancer Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. (13) Bone Marrow Transplantation Cancer Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. (14) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. (15) Cancer Research Center of Toulouse, INSERM UMR 1037, Institut Universitaire du Cancer, Toulouse, France. (16) School of Medicine, Cancer Immunoregulation and Immunotherapy Laboratory, The University of Queensland, QIMR Berghofer Medical Research Institute, Herston, Australia. (17) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia. (18) Cancer Research Center of Toulouse, INSERM UMR 1037, Institut Universitaire du Cancer, Toulouse, France. (19) Immunology in Cancer and Infection Laboratory, School of Medicine, QIMR Berghofer Medical Research Institute, The University of Queensland, Herston, Australia; mark.smyth@qimrberghofer.edu.au.
