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

The function of senescent-like T cells, transcriptomic features of immune effector senescence (IES) and their influence on therapeutic response were investigated in independent AML clinical cohorts comprising 1,864 patients treated with chemotherapy and/or immune checkpoint blockade (ICB). We show that senescent-like bone marrow CD8+ T cells are impaired in killing autologous AML blasts, and that their proportion negatively correlates with overall survival (OS). We define new IES signatures using two gene expression platforms and report that IES scores correlate with adverse-risk molecular lesions, stemness, and poor outcomes as a potentially more powerful predictor of OS than 2017-ELN risk or LSC17 stemness score. IES expression signatures also identify an ICB- unresponsive tumor microenvironment and predict significantly worse OS in AML as well as in solid tumors. The newly described IES scores provide improved AML risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit. ### Competing Interest Statement I.G. received research support from Merck (clinical study #[NCT02845297][1]). L.L. received research support from Genentech (imCORE grant #ML40354). ### Funding Statement S.R.; J.V. 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 Universitys School of Science and Technology. S.K.T. was supported for these studies by NIH/NCI 1U01CA232486 and U01CA243072; Department of Defense Translational Team Science Award CA180683P1; Andrew McDonough B+ Foundation; Gabrielles Angel Foundation for Cancer Research; Rally Foundation for Childhood Cancer Research; and the St Baldricks 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 Childrens Hospital of Philadelphias Center for Childhood Cancer Research. L.L. was supported for these studies by NIH/NCI P01CA225618. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Primary patient specimens (non-promyelocytic AML) and associated clinical data were obtained via informed consent in accordance with the Declaration of Helsinki on research protocols approved by the Ethics Committee of TU Dresden and Studienallianz Leukaemie (Germany) (EK98032010) and by the Childrens Hospital of Philadelphia (10-007767) and Johns Hopkins University (JHU) Institutional Review Boards. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The transcriptomic datasets generated in this study have been deposited on to the GEO repository under accession numbers GSE176100 and GSE178926 and will be publicly available as of the date of publication. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02845297&atom=%2Fmedrxiv%2Fearly%2F2022%2F02%2F09%2F2022.02.08.22270578.atom