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.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 20

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

×

Figure 8

Immunological control of myeloma is IFN-γ dependent.

Options: View larger image (or click on image) Download as PowerPoint
Immunological control of myeloma is IFN-γ dependent. (A–C) MM-bearing or...
(A–C) MM-bearing or MM-free B6.WT mice were transplanted as previously described, and IFN-γ production was determined ex vivo 8 weeks later. (A) Representative histograms, (B) geometric MFI, and (C) absolute numbers of IFN-γ–producing CD8+ T cells in mice with active myeloma progression (MM-relapsed) or controlled disease (MM-controlled) and in transplant control mice (MM-free) (MFI, n = 5–10 from 2 experiments; absolute number, n = 7–12 combined from 3 experiments). (D) Tumor burden and survival of MM-bearing recipient mice transplanted with BM and T cells from B6.WT, B6.IFN-γ–/–, or B6.IFN-γR–/– donors (n = 20 combined from 4 experiments). Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by log-rank test for survival data and Mann-Whitney U test for 2-sample and ANOVA for multiple-sample comparisons.