Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for multiple myeloma (MM) patients and is thought to prolong 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 recipients and donors that were myeloma-naïve or were myeloma-experienced to simulate autologous transplantation. Surprisingly, we demonstrate broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naïve T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct 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 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 IFNγ secretion and signaling was critical to protective immunity, and was profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and suggests rational approaches to improving clinical outcome.
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