Description
Stem cell transplantation establishes T cell-dependent myeloma immune-equilibrium that can be enhanced with immunotherapy
Simone A. Minnie1,2 Slavica Vuckovic,1 David Smith,1 Kate H. Gartlan,1,2 Thomas S. Watkins,1,3 Kate A. Markey,1,2 Camille Guillerey,1 Rachel D. Kuns,1 Ping Zhang,1 Marta Chesi,7 John J. Miles,3 Mark J. Smyth1 and Geoffrey R. Hill1,5
1QIMR Berghofer Medical Research Institute, Brisbane, QLD, AUSTRALIA; 2 The University of Queensland, QLD, AU; 3Centre for Biodiscovery and Molecular Development of Therapeutics, AITHM, James Cook University, QLD, AU; 4Comprehensive Cancer Center, Mayo Clinic, Arizona, USA; 5Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, QLD, AU
Autologous stem cell transplantation (ASCT) remains a standard treatment for myeloma (MM) patients, allows intensive cytoreduction and induces inflammation in the context of lymphodepletion. We thus hypothesized that SCT may overcome myeloma-induced immune defects to restore immune-equilibrium. To address this, we developed a preclinical model of ASCT for MM using Vk*MYC myeloma. Surprisingly, we demonstrate the induction of T cell-dependent MM control after SCT as recipients of bone marrow (BM) grafts containing T cells had prolonged survival and reduced myeloma burden compared to BM alone. This anti-myeloma activity was independent of γδ T, natural killer (NK) and NK T cells and was dependent on CD8+ T cells. TCR sequencing of CD8+ T cells from mice with controlled MM revealed a higher clonotype overlap relative to myeloma-free SCT recipients, consistent with myeloma-specific T cells. Furthermore, myeloma-primed T cells protected against relapse in secondary recipients and were Vk*MYC clone-specific. Despite T cell-dependent anti-myeloma immunity, some mice still relapse after SCT. Interestingly, IFNγ production, which was critical for protective immunity, was impaired in CD8+ T cells from mice with relapsed MM compared to those with controlled MM. Importantly, CD8+ T cell-derived IFNγ production could be enhanced by treatment with a CD137 agonist such that majority of treated animals had long-term disease control. Additionally, myeloma progression resulted in expression of numerous inhibitory receptors on CD8+ T cells and treatment with anti-PD-1 after SCT dramatically prolonged survival. These data provide new insight into the mechanisms of action of SCT in MM and suggests rational approaches to improving clinical outcome.