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

Simone A. Minnie, Rachel D. Kuns, Kate H. Gartlan, Ping Zhang, Andrew N. Wilkinson, Luke Samson, Camille Guillerey, Christian Engwerda, Kelli P.A. MacDonald, Mark J. Smyth, Kate A. Markey, Slavica Vuckovic and Geoffrey R. Hill

Key points

  • Myeloma promotes CD8+ T-cell exhaustion and IL-10 secretion from dendritic cells.

  • PD-1 and TIGIT-targeted checkpoint inhibition is effective after SCT.

Abstract

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.

  • Submitted January 4, 2018.
  • Accepted August 9, 2018.