title: PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation.
abstract: Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation.
authors.affiliation: 1] Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA [2] Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Claxton
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Ehmann
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: W B
authors.initials: WB
authors.lastname: Rybka
authors.affiliation: 1] Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA [2] Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Zeng
authors.affiliation: 1] Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA [2] Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Schell
authors.affiliation: Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor