Immune dysfunction signatures predict outcomes and define checkpoint blockade–unresponsive microenvironments in acute myeloid leukemia

Sergio Rutella, Jayakumar Vadakekolathu, Francesco Mazziotta, Stephen Reeder, Tung On Yau, Rupkatha Mukhopadhyay, Benjamin Dickins, Heidi Altmann, Michael Kramer, Hanna A. Knaus, Bruce R. Blazar, Vedran Radojcic, Joshua F. Zeidner, Andrea Arruda, Bofei Wang, Hussein A. Abbas, Mark D. Minden, Sarah K. Tasian, Martin Bornhäuser, Ivana GojoLeo Luznik

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

BACKGROUND. Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8+ T cells and whether they have prognostic relevance. METHODS. We analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB). RESULTS. We show that senescent-like bone marrow CD8+ T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival (OS). We defined what we believe to be new immune effector dysfunction (IED) signatures using 2 gene expression profiling platforms and reported that IED scores correlated with adverse-risk molecular lesions, stemness, and poor outcomes; these scores were a more powerful predictor of OS than 2017-ELN risk or leukemia stem cell (LSC17) scores. IED expression signatures also identified an ICB-unresponsive tumor microenvironment and predicted significantly shorter OS. CONCLUSION. The IED scores provided improved AML-risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit. TRIAL REGISTRATION. ClinicalTrials.gov; NCT02845297. FUNDING. John and Lucille van Geest Foundation, Nottingham Trent University’s Health & Wellbeing Strategic Research Theme, NIH/NCI P01CA225618, Genentech-imCORE ML40354, Qatar National Research Fund (NPRP8-2297-3-494).

Original languageEnglish (US)
Article numbere159579
JournalJournal of Clinical Investigation
Volume132
Issue number21
DOIs
StatePublished - Nov 1 2022

Bibliographical note

Funding Information:
Authorship note: SR and LL contributed equally to this work. Conflict of interest: LL received research support from Genentech (imCORE grant ML40354). Copyright: © 2022, Rutella et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: February 22, 2022; Accepted: September 6, 2022; Published: November 1, 2022. Reference information: J Clin Invest. 2022;132(21):e159579. https://doi.org/10.1172/JCI159579.

Funding Information:
S Rutella, JV, and S Reeder were supported for these studies by the Qatar National Research Fund (NPRP8-2297-3-494), the John and Lucille van Geest Foundation, and Nottingham Trent University’s Health & Wellbeing Strategic Research Theme. SKT is the Joshua Kahan Endowed Chair of Pediatric Leukemia Research at the Children’s Hospital of Philadelphia and was supported for these studies by the Leukemia and Lymphoma Society (Scholar Award), NIH/NCI 1U01CA232486 and U01CA243072, Department of Defense Translational Team Science Award CA180683P1, Andrew McDonough B+ Foundation, Gabrielle’s Angel Foundation for Cancer Research, Rally Foundation for Childhood Cancer Research, and the St Baldrick’s Foundation/ Stand Up to Cancer Pediatric Dream Team. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Childhood leukemia specimen banking was supported by the Children’s Hospital of Philadelphia’s Center for Childhood Cancer Research. LL was supported for these studies by NIH/NCI P01CA225618. HAA was supported for these studies by ASCO Conquer Cancer Foundation and Ladies Leukemia League. IG and JFZ were partly supported for these studies by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. (ClinicalTrials.org NCT02845297). VR was supported for these studies by NIH/NHLBI K08HL145116, a Career Development Award from the American Society for Transplantation and Cellular Therapy, and by the Huntsman Cancer Foundation, University of Utah, and Huntsman Cancer Institute Shared Resource Services (NIH/NCI P30CA042014; NIH/NCI 1S10RR026802-01).

Publisher Copyright:
© 2022, Rutella et al.

Keywords

  • Humans
  • Leukemia, Myeloid, Acute/therapy
  • Prognosis
  • Immunotherapy
  • Tumor Microenvironment
  • CD8-Positive T-Lymphocytes
  • Immune System Diseases

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Journal Article
  • Research Support, N.I.H., Extramural

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