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 5

Donor-derived IL-17A promotes myeloma relapse after BMT.

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Donor-derived IL-17A promotes myeloma relapse after BMT. (A) Tumor burde...
(A) Tumor burden, quantified and modeled using M-band levels as described, and survival in MM-bearing recipients transplanted with BM and T cells from WT or IL-17A–deficient (IL-17A–/–) donors (n = 20 combined from 4 experiments). (B) M-band of MM-bearing BMT+ with myeloma-experienced donors that were treated twice a week with 150 μg i.p of an IL-17A–blocking Ab or isotype control (cIg) from day 0 to week 6 after BMT+ (n = 12–13 combined from 2 experiments). (C–E) MM-free and MM-bearing recipient mice were transplanted with BM and T cells from IL-17ACreRosa26eYFP donors. eYFP+ cells were analyzed in BM (femur) and spleens 6 weeks after BMT. Representative dot plot (concatenated BM) and (C) total eYFP+ frequency and numbers, (D) frequency of TCRγδ+ and TCRβ+ cells within the eYFP+ cell population, and (E) total numbers of Th17 (eYFP+TCRβ+CD4+) and Tc17 (eYFP+TCRβ+CD8+) cells (n = 9 combined from 2 experiments). Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by log-rank test for survival and Mann-Whitney U test for numerical values.