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

    Author(s)
    Minnie, Simone A
    Kuns, Rachel D
    Gartlan, Kate H
    Zhang, Ping
    Wilkinson, Andrew N
    Samson, Luke
    Guillerey, Camille
    Engwerda, Christian
    MacDonald, Kelli PA
    Smyth, Mark J
    Markey, Kate A
    Vuckovic, Slavica
    Hill, Geoffrey R
    Griffith University Author(s)
    Engwerda, Christian R.
    MacDonald, Kelli P.
    Year published
    2018
    Metadata
    Show full item record
    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 ...
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    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.
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    Journal Title
    Blood
    Volume
    132
    Issue
    16
    DOI
    https://doi.org/10.1182/blood-2018-01-825240
    Subject
    Cardiovascular medicine and haematology
    Clinical sciences
    Science & Technology
    Life Sciences & Biomedicine
    Hematology
    STIMULATING FACTOR-1 RECEPTOR
    TUMOR-ASSOCIATED MACROPHAGES
    Publication URI
    http://hdl.handle.net/10072/401153
    Collection
    • Journal articles

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