Immune Dysfunction Signatures Predict Outcomes and Define Checkpoint Blockade-Unresponsive Microenvironments in Acute Myeloid Leukemia

Authors

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 Gojo
Leo Luznik

Publication Date

11-1-2022

Journal

Journal of Clinical Investigation

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).

Keywords

Humans, Leukemia, Myeloid, Acute, Prognosis, Immunotherapy, Tumor Microenvironment, CD8-Positive T-Lymphocytes, Immune System Diseases, Cancer immunotherapy, Cellular senescence, Leukemias, Hematology

DOI

10.1172/JCI159579

PMID

36099049

PMCID

PMC9621145

PubMedCentral® Posted Date

11-1-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes