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

Autologous stem cell transplantation (auto-SCT) remains a standard of care for multiple myeloma patients and prolongs progression-free survival. A small cohort of patients achieve long-term control of disease, however 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 co-stimulatory/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 immunoglobulin and ITIM domains (TIGIT), programmed death 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 CSF-1R-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.