@article{626e0552877c404f9873f98841dd7ba4,
title = "Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia",
abstract = "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.",
keywords = "AML, Checkpoint blockade, Immune microenvironment, Leukemia, T cell",
author = "Lamble, {Adam J.} and Yoko Kosaka and Ted Laderas and Allie Maffit and Andy Kaempf and Brady, {Lauren K.} and Weiwei Wang and Nicola Long and Saultz, {Jennifer N.} and Motomi Mori and David Soong and LeFave, {Clare V.} and Fei Huang and Homer Adams and Loriaux, {Marc M.} and Loriaux, {Marc M.} and Tognon, {Cristina E.} and Pierrette Lo and Tyner, {Jeffrey W.} and Tyner, {Jeffrey W.} and Guang Fan and McWeeney, {Shannon K.} and Druker, {Brian J.} and Druker, {Brian J.} and Druker, {Brian J.} and Lind, {Evan F.} and Lind, {Evan F.} and Lind, {Evan F.}",
note = "Funding Information: 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. Funding Information: ACKNOWLEDGMENTS. The authors thank all the patients whose generous donation of their bone marrow and blood made these studies possible, and the clinical and laboratory personnel who procured and processed the specimens used in our studies. This work was funded in part by generous support from the Leukemia and Lymphoma Society of America Beat AML project (Principal Investigators B.J.D. and J.W.T.). A.M. was supported by the Department of Pediatrics Biostatistics Pilot Grant, Oregon Health & Science University. J.W.T. received grants from the V Foundation for Cancer Research, the Gabrielle{\textquoteright}s Angel Foundation for Cancer Research, and the National Cancer Institute (1R01CA183947, 1U01CA217862, 1U54CA224019). E.F.L. is supported by Grants U54CA224019 and U01CA217862 from the National Cancer Institute (Co-investigator). A.K. and M.M. are supported by NIH/National Cancer Institute Cancer Center Support Grant P30CA069533.",
year = "2020",
month = jun,
day = "23",
doi = "10.1073/pnas.1916206117",
language = "English (US)",
volume = "117",
pages = "14331--14341",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "25",
}