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 October 9, 2018
Citation Information: J Clin Invest. 2019;129(1):106-121. https://doi.org/10.1172/JCI98888.
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Research Article Immunology

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 9

CD137 costimulation promotes long-term eradication of myeloma after BMT.

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CD137 costimulation promotes long-term eradication of myeloma after BMT....
MM-bearing recipient mice were transplanted with BM and T cells from B6.WT donors. Agonistic CD137 (clone 3H3) or a control mAb (IgG2a) was administered from week 2 to week 6 after BMT. (A) Illustration of experimental design. (B) Tumor burden, quantified using M-band levels as described, and (C) overall survival (n = 18 combined from 2 experiments). (D–G) BM and spleens were harvested after treatment ceased, and cells were analyzed using flow cytometry (n = 5–10 from 1 to 2 experiments). (D) Percentage of CD138+CD19– myeloma cells in BM. (E) Absolute numbers of CD3+, CD8+, and CD4+ T cells and frequency of FoxP3+ within CD4+ T cells in BM and spleens. (F) Representative histograms show KLRG1 expression in CD8+ T cells and absolute numbers of KLRG1+ cells within CD8+ and CD4+ T cells in BM. (G) Representative histograms show GrB, IFN-γ, and CD107a expression in CD8+ T cells and graphs show absolute numbers of GrB+, IFN-γ+, and CD107a+CD8+ T cells and GrB+ and IFN-γ+CD4+ T cells in BM. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by log-rank test for survival data and Mann-Whitney U test for numerical values.