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 2

Donor memory T cells limit myeloma progression after BMT with myeloma-experienced T cells.

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Donor memory T cells limit myeloma progression after BMT with myeloma-ex...
(A) Representative FACS plots and frequency of TCM (CD44+CD62L+) and TEM/EFF (CD44+CD62L–) cells in naive and myeloma-experienced donor grafts (n = 3 per group). (B–F) MM-bearing recipients were lethally irradiated and transplanted with 10 × 106 TCD-BM cells alone (TCD-BMT) or 3 × 106 CD44+ or CD44– T cells from CD45.1/CD45.2 myeloma-experienced donors. (B) Tumor burden, quantified and modeled using M-band levels as described, and survival of Vk12653-bearing recipients (n = 14–16 combined from 2 experiments). (C and D) Recipients were sacrificed 2 weeks after BMT+, and BM T cells were analyzed by flow cytometry (n = 5 per group from 1 experiment). (C) Absolute numbers of donor CD8+ and CD4 + T cells and TCM and TEM/EFF CD8+ T cells in BM. (D) Representative FACS plots and absolute numbers of DNAM-1+PD-1+ and exhausted (DNAM-1–PD-1+TIM-3+) donor CD8+ T cells. (E and F) Recipients of BMT+-CD44+ grafts were sacrificed more than 100 days after BMT+, and BM T cells were analyzed via flow cytometry (n = 6 from 1 experiment). (E) Absolute numbers of donor CD8+ and CD4+ T cells. (F) Representative FACS plot and absolute numbers of TCM and TEM/EFF donor CD8+ T cells. 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 2-sample and ANOVA for multiple-sample comparisons.