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

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 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.

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

“…TIGIT can bind to both PVR and CD226, and prevention of CD226‐dimerization on the T‐cell surface is one of the key cell‐intrinsic regulatory mechanisms of TIGIT . In addition, TIGIT is co‐expressed with PD1 on exhausted CD8 T cells, and TIGIT + CD8 + T cells present a severely dysfunctional state with diminished cytokine production and proliferation . Preclinical studies with Tigit −/− mice or anti‐TIGIT mAb treatment have been shown to greatly improve anti‐tumor immune responses in a CD8 + T‐cell‐dependent manner .…”

“…54,55 Preclinical studies with Tigit À/À mice or anti-TIGIT mAb treatment have been shown to greatly improve anti-tumor immune responses in a CD8 + T-cell-dependent manner. 54 Hence, TIGIT has been implicated as one of the potential cancer immunotherapeutic targets to elicit effective anti-tumor immunity (Table 1).…”

Immunotherapy for Multiple Myeloma

“…In an in vivo murine myeloma model, CD8 + T cells in the bone marrow of MM-relapsed mice expressed higher levels of TIGIT and lower levels of another receptor of CD155, DNAM-1, which can deliver a positive signal in T cells through the binding of CD155, compared with those in control or MM-controlled mice. Anti-TIGIT monoclonal antibody decreased myeloma cells in bone marrow and prolonged survival compared with control-Ig or anti-PD-1 monoclonal antibody-treated mice [103], suggesting that TIGIT expression is more dominant than PD-1 in the immunosuppressive function in MM. A clinical trial using anti-TIGIT monoclonal antibody in advanced solid tumors is underway (NCT04047862, NCT03563716).…”

Versican Proteolysis Predicts Immune Effector Infiltration and Post-Transplant Survival in Myeloma

“…Early phase clinical data demonstrated the promise of post-ASCT vaccination with a DC-myeloma cell fusion product (29). Despite recent concerns about PD-1 pathway-targeting checkpoint inhibition in myeloma, other checkpoint pathways (e.g., TIGIT) are ripe for clinical testing (9,10). We propose that risk stratification via VCAN proteolysis staining will pinpoint the patients most likely to benefit from these cutting-edge immunotherapies.…”

“…In contrast to disseminated hematological malignancies where immunological tolerance is attributable to defective T effector priming and anergy (7), myeloma is characterized by intratumoral effector dysfunction, mirroring solid tumor dynamics (8). Myeloma relapses post-ASCT are heralded by the emergence of dysfunctional (exhausted/senescent) T cells expressing programmed death -1 (PD- 1) and T-cell immunoglobulin and ITIM domain (TIGIT) receptors as well as IL-10secreting myeloid cells (9)(10)(11)(12)(13). However, it is not a priori clear, which patients will progress after ASCT.…”