Bone marrow transplantation generates T cell–dependent control of myeloma in mice
Slavica Vuckovic, … , Mark J. Smyth, Geoffrey R. Hill
Slavica Vuckovic, … , Mark J. Smyth, Geoffrey R. Hill
Published January 2, 2019; First published October 9, 2018
Citation Information: J Clin Invest. 2019;129(1):106-121. https://doi.org/10.1172/JCI98888.
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Categories: Research Article Immunology Transplantation

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.

Authors

Slavica Vuckovic, Simone A. Minnie, David Smith, Kate H. Gartlan, Thomas S. Watkins, Kate A. Markey, Pamela Mukhopadhyay, Camille Guillerey, Rachel D. Kuns, Kelly R. Locke, Antonia L. Pritchard, Peter A. Johansson, Antiopi Varelias, Ping Zhang, Nicholas D. Huntington, Nicola Waddell, Marta Chesi, John J. Miles, Mark J. Smyth, Geoffrey R. Hill

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Figure 1

Donor T cells provide immune-mediated control of myeloma after BMT.

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Donor T cells provide immune-mediated control of myeloma after BMT. MM-b...
MM-bearing recipients were lethally irradiated and transplanted with 10 × 106 BM cells with or without 5 × 106 T cells from naive or myeloma-experienced donors. Mice were monitored for survival and tumor burden using M-band (G/A) levels. M-band levels were modeled to calculate a predictive rate of tumor growth (solid line), with shaded CIs and the M-band relapse threshold shown as a dotted line. (A) Tumor burden and survival of Vk12653-bearing recipients (n = 30; combined from 5 experiments) and (B) survival of Vk12598-bearing recipients (n = 10; combined from 2 experiments) that received TCD-BMT or BM and T cells from naive donors (BMT). (C) Tumor burden and survival of Vk12653-bearing recipients (n = 16–19 combined from 3 experiments) and (D) survival of Vk12598-bearing recipients (n = 12 combined from 2 experiments) transplanted with TCD-BMT, BMT, or TCD-BM with myeloma-experienced T cells (BMT+). (E) Tumor burden and survival of Vk12653-bearing recipients treated with saline or CD8- or CD4-depleting Abs (αCD8, αCD4) from day 0 to 8 weeks after BMT (n = 11 combined from 2 experiments). (F) Survival of Vk12653-bearing recipients of BMT grafts from NK cell–intact (Mcl1fl/fl or WT) or NK cell–deficient (NKp46CreMcl1fl/fl) donors (n = 18 combined from 2 experiments). To determine statistical significance, the tumor burden was plotted using longitudinal mixed-effects linear models, and survival was analyzed using a log-rank test. *P < 0.05 and ***P < 0.001.