title: T-cell Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of Immunotherapy.
abstract: Multiple myeloma is the most common indication for high-dose chemotherapy and autologous stem cell transplantation (ASCT), and lenalidomide maintenance after transplant is now standard. Although lenalidomide doubles progression-free survival, almost all patients eventually relapse. Posttransplant immunotherapy to improve outcomes after ASCT therefore has great merit but first requires delineation of the dynamics of immune reconstitution. We evaluated lymphocyte composition and function after ASCT to guide optimal timing of immunotherapy and to identify potential markers of relapse. Regulatory T cells (Treg) decline as CD8(+) T cells expand during early lymphocyte recovery after ASCT, markedly reducing the Treg:CD8(+) effector T-cell ratio. These CD8(+) T cells can respond to autologous dendritic cells presenting tumor antigen in vitro as early as day +12 after transplant, becoming antigen-specific cytolytic T-lymphocyte effectors and thereby demonstrating preservation of cellular reactivity. CD4(+) and CD8(+) T cells express the negative regulatory molecules, CTLA-4, PD-1, LAG-3, and TIM-3, before and after ASCT. A subpopulation of exhausted/senescent CD8(+) T cells, however, downregulates CD28 and upregulates CD57 and PD-1, characterizing immune impairment and relapse after ASCT. Relapsing patients have higher numbers of these cells at +3 months after transplant, but before detection of clinical disease, indicating their applicability in identifying patients at higher risk of relapse. PD-1 blockade also revives the proliferation and cytokine secretion of the hyporesponsive, exhausted/senescent CD8(+) T cells in vitro. Collectively, these results identify T-cell exhaustion/senescence as a distinguishing feature of relapse and support early introduction of immunotherapy to stimulate antitumor immunity after ASCT.
authors.affiliation: Laboratory of Cellular Immunobiology, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. The Rockefeller University, New York, New York. Weill Cornell Medical College, New York, New York. chungd1@mskcc.org.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chung
authors.affiliation: Laboratory of Cellular Immunobiology, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Pronschinske
authors.affiliation: Laboratory of Cellular Immunobiology, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Shyer
authors.affiliation: Laboratory of Cellular Immunobiology, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sneh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Laboratory of Cellular Immunobiology, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Samantha
authors.initials: S
authors.lastname: Leung
authors.affiliation: Laboratory of Cellular Immunobiology, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Curran
authors.affiliation: Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Lesokhin
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Devlin
authors.affiliation: Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Giralt
authors.affiliation: Laboratory of Cellular Immunobiology, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. Adult Bone Marrow Transplant Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. The Rockefeller University, New York, New York. Weill Cornell Medical College, New York, New York. Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York.
authors.forename: James W
authors.initials: JW
authors.lastname: Young
mesh_terms: D000328:Adult; D000368:Aged; D064592:Autografts; D016516:CD4-CD8 Ratio; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology* / Q000628:therapy; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000517:prevention & control; D033581:Stem Cell Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology