Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion

Pavan Bachireddy, Ursula Hainz, Michael Rooney, Olga Pozdnyakova, Julie Aldridge, Wandi Zhang, Xiaoyun Liao, F. Stephen Hodi, Karyn O'Connell, W. Nicholas Haining, Natalie R. Goldstein, Christine M. Canning, Robert J. Soiffer, Jerome Ritz, Nir Hacohen, Edwin P. Alyea, Haesook T. Kim, Catherine J. Wu

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1412-1421
Number of pages10
JournalBlood
Volume123
Issue number9
DOIs
StatePublished - Feb 27 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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