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dc.contributor.authorMinnie, Simone A
dc.contributor.authorKuns, Rachel D
dc.contributor.authorGartlan, Kate H
dc.contributor.authorZhang, Ping
dc.contributor.authorWilkinson, Andrew N
dc.contributor.authorSamson, Luke
dc.contributor.authorGuillerey, Camille
dc.contributor.authorEngwerda, Christian
dc.contributor.authorMacDonald, Kelli PA
dc.contributor.authorSmyth, Mark J
dc.contributor.authorMarkey, Kate A
dc.contributor.authorVuckovic, Slavica
dc.contributor.authorHill, Geoffrey R
dc.description.abstractAutologous 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.
dc.publisherAmerican Society of Hematology
dc.subject.fieldofresearchCardiovascular medicine and haematology
dc.subject.fieldofresearchClinical sciences
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.titleMyeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationMinnie, SA; Kuns, RD; Gartlan, KH; Zhang, P; Wilkinson, AN; Samson, L; Guillerey, C; Engwerda, C; MacDonald, KPA; Smyth, MJ; Markey, KA; Vuckovic, S; Hill, GR, Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade, Blood, 2018, 132 (16), pp. 1675-1688
gro.hasfulltextNo Full Text
gro.griffith.authorEngwerda, Christian R.
gro.griffith.authorMacDonald, Kelli P.

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