Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade

Abstract

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.

Autologous graft versus myeloma: it’s not a myth

“…Guillerey et al recently reported that the exhaustion marker TIGIT was upregulated on CD8 + T cells during disease progression (8). This TIGIT expression was also the reason for disease relapse in autologous transplantation in the Vk*MYC mouse (9). However, Vuckovic and colleagues did not mention TIGIT in this study.…”

Immunotherapy for Multiple Myeloma

“…Exhausted effector T cells expressing CD28 -LAG3 + TIGIT + were increased in MM patient's refractory to DARA combined with pomalidomide [102]. The percentages of TIGIT + CD8 + T cells and their expression levels were increased in patients with NDMM and RRMM [82]. 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.…”

“…Exhausted T cells expressing immune checkpoint receptors are involved in disease progression in cancer models, although the role of exhausted T cells in the pathophysiology of MM remains controversial [15,80,81]. An in vivo murine myeloma model demonstrated that the expression levels of immune checkpoint receptors such as programmed cell death protein 1 (PD-1), T-cell immunoglobulin and ITIM domains (TIGIT), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin mucin-3 (Tim-3) were increased on CD8 + T cells in bone marrow in MM-relapsed mice compared with those in control mice and MM-controlled mice [82]. PD-L1 (CD274) was first identified as a homologue of the B7 family and named B7-H1 by our group [83,84].…”

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.…”