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TIGIT immune checkpoint blockade restores CD8+ T cell immunity against multiple myeloma

Camille Guillerey, Heidi Harjunpää, Nadège Carrié, Sahar Kassem, Tricia Teo, Kim Miles, Sophie Krumeich, Marianne Weulersse, Marine Cuisinier, Kimberley Stannard, Yuan Yu, Simone A. Minnie, Geoffrey R. Hill, William C. Dougall, Hervé Avet-Loiseau, Michele W.L. Teng, Kyohei Nakamura, Ludovic Martinet and Mark J. Smyth

Key points

  • TIGIT expression is up-regulated on CD8+ T cells during MM progression and is associated with impaired effector functions.

  • TIGIT-deficiency or -blockade protects mice against multiple myeloma and improves effector functions of myeloma patient CD8+ T cells.

Abstract

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.

  • Submitted January 4, 2018.
  • Accepted June 27, 2018.