Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia.
AML
T cell
checkpoint blockade
immune microenvironment
leukemia
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
23 06 2020
23 06 2020
Historique:
pubmed:
10
6
2020
medline:
29
8
2020
entrez:
10
6
2020
Statut:
ppublish
Résumé
Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with approximately four new cases per 100,000 persons per year. Standard treatment for AML consists of induction chemotherapy with remission achieved in 50 to 75% of cases. Unfortunately, most patients will relapse and die from their disease, as 5-y survival is roughly 29%. Therefore, other treatment options are urgently needed. In recent years, immune-based therapies have led to unprecedented rates of survival among patients with some advanced cancers. Suppression of T cell function in the tumor microenvironment is commonly observed and may play a role in AML. We found that there is a significant association between T cell infiltration in the bone marrow microenvironment of newly diagnosed patients with AML and increased overall survival. Functional studies aimed at establishing the degree of T cell suppression in patients with AML revealed impaired T cell function in many patients. In most cases, T cell proliferation could be restored by blocking the immune checkpoint molecules PD-1, CTLA-4, or TIM3. Our data demonstrate that AML establishes an immune suppressive environment in the bone marrow, in part through T cell checkpoint function.
Identifiants
pubmed: 32513686
pii: 1916206117
doi: 10.1073/pnas.1916206117
pmc: PMC7321988
doi:
Substances chimiques
CTLA-4 Antigen
0
CTLA4 protein, human
0
Cytokines
0
HAVCR2 protein, human
0
Hepatitis A Virus Cellular Receptor 2
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14331-14341Subventions
Organisme : NCI NIH HHS
ID : P30 CA069533
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217862
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224019
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA108947
Pays : United States
Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: L.K.B., F.H., D.S., and H.A. are employees of Janssen Pharmaceuticals R&D, LLC. D.S. is currently an employee and holds stock in Genmab. C.V.L is an employee of Lab Connect LLC. J.N.S. receives research support form Kyn Therapeutics. B.J.D. has the following disclosures: Scientific Advisory Board for Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); Scientific Advisory Board and Stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Iterion Therapeutics, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); Scientific Founder: MolecularMD (inactive, acquired by ICON); Board of Directors and Stock: Amgen; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Founder: VB Therapeutics; Clinical Trial Funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and Oregon Health & Science University and Dana-Farber Cancer Institute (one Merck exclusive license). J.W.T. receives research support from Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Petra, Seattle Genetics, Syros, and Takeda. J.W.T. is a cofounder of Leap Oncology. E.F.L. receives research support from Janssen Pharmaceuticals, Celgene Amgen, and Kyn Therapeutics.
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