Bone marrow transplantation generates T cell-dependent control of myeloma in mice Journal Article

Authors: Vuckovic, S.; Minnie, S. A.; Smith, D.; Gartlan, K. H.; Watkins, T. S.; Markey, K. A.; Mukhopadhyay, P.; Guillerey, C.; Kuns, R. D.; Locke, K. R.; Pritchard, A. L.; Johansson, P. A.; Varelias, A.; Zhang, P.; Huntington, N. D.; Waddell, N.; Chesi, M.; Miles, J. J.; Smyth, M. J.; Hill, G. R.
Article Title: Bone marrow transplantation generates T cell-dependent control of myeloma in mice
Abstract: Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk∗MYC myeloma-bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell-dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes. © 2019 American Society for Clinical Investigation. All rights reserved.
Journal Title: Journal of Clinical Investigation
Volume: 129
Issue: 1
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2019-01-01
Start Page: 106
End Page: 121
Language: English
DOI: 10.1172/jci98888
PUBMED: 30300141
PROVIDER: scopus
PMCID: PMC6307976
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
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MSK Authors
  1. Kate Ann Markey
    10 Markey