Immune-based therapies hold promise for the treatment of multiple myeloma (MM), but so far, immune checkpoint blockade targeting programmed cell death protein 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 monoclonal immunoglobulin protein levels associated with reduced tumor burden and prolonged survival, indicating that TIGIT limits antimyeloma immune responses. Importantly, blocking TIGIT using monoclonal antibodies 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.

Autologous stem cell transplantation (SCT) remains a standard of care for multiple myeloma (MM) patients and prolongs progression-free survival. A small cohort of patients achieve long-term control of disease, but the majority of patients ultimately relapse, and the mechanisms permitting disease progression remain unclear. In this study, we used a preclinical model of autologous SCT for myeloma where the disease either progressed (MM relapsed) or was controlled. In the bone marrow (BM), inhibitory receptor expression on CD8 T cells correlated strongly with myeloma progression after transplant. In conjunction, the costimulatory/adhesion receptor CD226 (DNAM-1) was markedly downregulated. Interestingly, DNAM-1 CD8 T cells in MM-relapsed mice had an exhausted phenotype, characterized by upregulation of multiple inhibitory receptors, including T-cell immunoglobulin and ITIM domains (TIGIT) and programmed cell death protein 1 (PD-1) with decreased T-bet and increased eomesodermin expression. Immune checkpoint blockade using monoclonal antibodies against PD-1 or TIGIT significantly prolonged myeloma control after SCT. Furthermore, CD8 T cells from MM-relapsed mice exhibited high interleukin-10 (IL-10) secretion that was associated with increased TIGIT and PD-1 expression. However, while donor-derived IL-10 inhibited myeloma control post-SCT, this was independent of IL-10 secretion by or signaling to T cells. Instead, the donor myeloid compartment, including colony-stimulating factor 1 receptor-dependent macrophages and an IL-10-secreting dendritic cell population in the BM, promoted myeloma progression. Our findings highlight PD-1 or TIGIT blockade in conjunction with SCT as a potent combination therapy in the treatment of myeloma.

had markedly impaired IFN-γ production, although this phenotype was reversible (13). Together, these studies indicate that T cell-dependent myeloma immunity is present, albeit suppressed, in patients with myeloma.NK cells play a key role in myeloma immunity, and NK dysfunction has been implicated in myeloma progression in nontransplanted myeloma-bearing mice (42). MGUS patients were found to have similar or increased numbers of NK cells compared with healthy donors, while patients with late-stage myeloma have significantly reduced NK cell numbers (43, 44). NK cells are particularly important in the context of treatment with immunomodulatory imide drugs (IMiDs), as IMiDs stimulate IL-2 production by T cells, resulting in NK cell activation and expansion (40,45,46). Furthermore, a recent study found that IMiDs prime myeloma for killing by daratumumab, a CD38-targeting mAb, by upregulating CD38 expression and sensitizing myeloma cells to NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) (47). A second antibody, elotuzumab, binds SLAMF7 on MM cells and Fc receptors (CD16) on NK cells and macrophages to promote ADCC and antibody-dependent cellular phagocytosis (48). This mAb does not have single-agent activity but is active in combination with IMiDs. NK cell-mediated myeloma immunity was addressed in a murine model of ASCT, and surprisingly, NK cells were not required for myeloma control in this setting (26). These data suggest that alternative mechanisms may underpin responses after ASCT, although this has yet to be definitively investigated in a clinical setting.

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