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.

DOI: 10.1182/blood-2013-08-523001

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@article{Bachireddy2014ReversalOI, title={Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion.}, author={Pavan Bachireddy and Ursula Hainz and Michael S. Rooney and Olga O. Pozdnyakova and Julie R Aldridge and Wandi Zhang and Xiaoyun Liao and Frank Stephen Hodi and Karyn E O'Connell and W. Nicholas Haining and Natalie R Goldstein and Christine M. Canning and Robert J . Soiffer and Jerome Ritz and Nir Hacohen and Edwin P Alyea and Haesook T Kim and Catherine J. Wu}, journal={Blood}, year={2014}, volume={123 9}, pages={1412-21} }