Signatures of immune dysfunction predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia

Rutella, S ORCID: https://orcid.org/0000-0003-1970-7375, Vadakekolathu, J ORCID: https://orcid.org/0000-0002-2671-4285, Mazziotta, F, Reeder, S, Yau, T-O ORCID: https://orcid.org/0000-0002-3283-0370, Mukhopadhyay, R, Dickins, B ORCID: https://orcid.org/0000-0002-0866-6232, Altmann, H, Kramer, M, Knaus, HA, Blazar, BR, Radojcic, V, Zeidner, JF, Arruda, A, Wang, B, Abbas, HA, Minden, MD, Tasian, SK, Bornhäuser, M, Gojo, I and Luznik, L, 2022. Signatures of immune dysfunction predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia. Journal of Clinical Investigation. ISSN 0021-9738

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Abstract

Background and methods: The functional and transcriptional features of immune effector senescence and their influence on therapeutic response were investigated in independent AML 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 new immune effector dysfunction (IED) signatures using two gene expression profiling platforms and report that IED scores correlated with adverse-risk molecular lesions, stemness, and poor outcomes as a potentially 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 worse OS.

Conclusion: The newly described IED scores provided improved AML risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit.

Item Type:	Journal article
Publication Title:	Journal of Clinical Investigation
Creators:	Rutella, S., Vadakekolathu, J., Mazziotta, F., Reeder, S., Yau, T.-O., Mukhopadhyay, R., Dickins, B., Altmann, H., Kramer, M., Knaus, H.A., Blazar, B.R., Radojcic, V., Zeidner, J.F., Arruda, A., Wang, B., Abbas, H.A., Minden, M.D., Tasian, S.K., Bornhäuser, M., Gojo, I. and Luznik, L.
Publisher:	American Society for Clinical Investigation
Date:	13 September 2022
ISSN:	0021-9738
Identifiers:	Number Type 10.1172/jci159579 DOI 1598012 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Jeremy Silvester
Date Added:	15 Sep 2022 09:05
Last Modified:	15 Sep 2022 09:09
URI:	https://irep.ntu.ac.uk/id/eprint/47034

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