Bone marrow transplantation generates T cell–dependent control of myeloma in mice

Vuckovic, Slavica, Minnie, Simone A., Smith, David, Gartlan, Kate H., Watkins, Thomas S., Markey, Kate A., Mukhopadhyay, Pamela, Guillerey, Camille, Kuns, Rachel D., Locke, Kelly R., Pritchard, Antonia L., Johansson, Peter A., Varelias, Antiopi, Zhang, Ping, Huntington, Nicholas D., Waddell, Nicola, Chesi, Marta, Miles, John J., Smyth, Mark J., and Hill, Geoffrey R. (2019) Bone marrow transplantation generates T cell–dependent control of myeloma in mice. Journal of Clinical Investigation, 129 (1). pp. 106-121.

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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.

Item ID: 56678
Item Type: Article (Research - C1)
ISSN: 1558-8238
Copyright Information: Copyright 2019, American Society for Clinical Investigation.
Funders: Cancer Council Queensland (CCQ), National Health and Medical Research Council (NHMRC), Cancer Australia (CA), Cure Cancer Australia (CCA), Can Too (CT)
Projects and Grants: NHMRC Early Career Fellowship 1107417, CA/CCA/CT PdCCRS grant 1122183, NHMRC Senior Principal Research Fellowship
Date Deposited: 12 Feb 2019 00:31
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified @ 100%
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