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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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 3

BMT generates protective myeloma-specific T cells.

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BMT generates protective myeloma-specific T cells. MM-bearing recipients...
MM-bearing recipients were transplanted with TCD-BM from naive mice and either naive T cells (naive) or T cells from MM-bearing recipients with long-term control of Vk12653 myeloma (>120 days after BMT: MM-exp). (A) Tumor burden, quantified and modeled using M-band levels as described, and survival of Vk12653-bearing recipients transplanted with either naive or MM-exp T cells (n = 14–18 combined from 2 experiments). (B) Representative FACS plots and frequency of TEM/EFF, TCM, and naive CD8+ T cells and (C) representative histograms and frequency of CD122+ cells within TCM CD8+ T cells in the BM of recipients of naive or MM-exp T cells, 120 days after BMT (naive, n = 4; MM-exp, n = 12 from 1 experiment). (D) Survival of Vk12653-bearing recipient mice and Vk12598-bearing recipient mice transplanted with naive TCD-BM and either naive T cells or MM-expT cells from mice with long-term control of Vk12653 myeloma (n = 10 combined from 2 experiments). (E) M-band 6 weeks after BMT of secondary recipients of naive TCD-BM and either naive T cells or 2 × 106 MM-exp CD8+ or 2 × 106 MM-exp CD4+ T cells transferred with naive CD4+ or CD8+ T cells, respectively (n = 10–11 combined from 2 experiments). Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by Mann-Whitney U test for numerical values and log-rank test for survival data.