title: Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion.
abstract: Increasing evidence across malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. We hypothesized that marrow-infiltrating immune populations play a critical role in response to donor lymphocyte infusion (DLI), an established and potentially curative immune therapy whose precise mechanism remains unknown. We therefore analyzed marrow-infiltrating immune populations in 29 patients (22 responders, 7 nonresponders) with relapsed chronic myelogenous leukemia who received CD4(+) DLI in the pre-tyrosine kinase inhibitor era. Immunohistochemical analysis of pretreatment marrow revealed that the presence of >4% marrow-infiltrating CD8(+) (but not CD4(+)) T cells predicted DLI response, even in the setting of high leukemia burden. Furthermore, mRNA expression profiling of marrow-infiltrating T cells of a subset of responders compared with nonresponders revealed enrichment of T-cell exhaustion-specific genes in pretreatment T cells of DLI responders and significant downregulation of gene components in the same pathway in responders in conjunction with clinical response. Our data demonstrate that response to DLI is associated with quantity of preexisting marrow CD8(+) T cells and local reversal of T-cell exhaustion. Our studies implicate T-cell exhaustion as a therapeutic target of DLI and support the potential use of novel anti-PD1/PDL1 agents in lieu of DLI.
authors.affiliation: Department of Medical Oncology and.
authors.forename: Pavan
authors.initials: P
authors.lastname: Bachireddy
authors.forename: Ursula
authors.initials: U
authors.lastname: Hainz
authors.forename: Michael
authors.initials: M
authors.lastname: Rooney
authors.forename: Olga
authors.initials: O
authors.lastname: Pozdnyakova
authors.forename: Julie
authors.initials: J
authors.lastname: Aldridge
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Karyn
authors.initials: K
authors.lastname: O'Connell
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Goldstein
authors.forename: Christine M
authors.initials: CM
authors.lastname: Canning
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
mesh_terms: D001782:Blood Donors; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D015331:Cohort Studies; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D017710:Lymphocyte Transfusion; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D013601:T-Lymphocytes / Q000473:pathology*; D059467:Transcriptome; D016896:Treatment Outcome; D047368:Tumor Burden