Bone marrow transplantation generates T cell-dependent control of myeloma in mice.

Autor: Vuckovic S; QIMR Berghofer Medical Research Institute, Brisbane, Australia.; Faculty of Medicine, The University of Queensland, Herston, Australia.; Multiple Myeloma Research Group, Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, Australia., Minnie SA; QIMR Berghofer Medical Research Institute, Brisbane, Australia.; Faculty of Medicine, The University of Queensland, Herston, Australia., Smith D; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Gartlan KH; QIMR Berghofer Medical Research Institute, Brisbane, Australia.; Faculty of Medicine, The University of Queensland, Herston, Australia.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Watkins TS; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Markey KA; QIMR Berghofer Medical Research Institute, Brisbane, Australia.; Faculty of Medicine, The University of Queensland, Herston, Australia.; Division of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Mukhopadhyay P; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Guillerey C; QIMR Berghofer Medical Research Institute, Brisbane, Australia.; Faculty of Medicine, The University of Queensland, Herston, Australia., Kuns RD; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Locke KR; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Pritchard AL; QIMR Berghofer Medical Research Institute, Brisbane, Australia.; Genetics and Immunology, University of the Highlands and Islands, Inverness, United Kingdom., Johansson PA; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Varelias A; QIMR Berghofer Medical Research Institute, Brisbane, Australia.; Faculty of Medicine, The University of Queensland, Herston, Australia., Zhang P; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Huntington ND; Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Department of Medical Biology and.; Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia., Waddell N; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Chesi M; Comprehensive Cancer Center, Mayo Clinic, Scottsdale, Arizona, USA., Miles JJ; Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Cairns, Australia., Smyth MJ; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Hill GR; QIMR Berghofer Medical Research Institute, Brisbane, Australia.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.; Department of Haematology, The Royal Brisbane and Women's Hospital, Brisbane, Australia.; Division of Medical Oncology, University of Washington, Seattle, Washington, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2019 Jan 02; Vol. 129 (1), pp. 106-121. Date of Electronic Publication: 2018 Nov 19.
DOI: 10.1172/JCI98888
Abstrakt: 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.
Databáze: MEDLINE