Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia

Adam J. Lamble; Yoko Kosaka; Ted Laderas; Allie Maffit; Andy Kaempf; Lauren K. Brady; Weiwei Wang; Nicola Long; Jennifer N. Saultz; Motomi Mori; David Soong; Clare V. LeFave; Fei Huang; Homer Adams; Marc M. Loriaux; Cristina E. Tognon; Pierrette Lo; Jeffrey W. Tyner; Guang Fan; Shannon K. McWeeney; Brian J. Druker; Evan F. Lind

doi:10.1073/pnas.1916206117

Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia

Adam J. Lamble
, Yoko Kosaka
, Ted Laderas
, Allie Maffit
, Andy Kaempf
, Lauren K. Brady
, Weiwei Wang
, Nicola Long
, Jennifer N. Saultz
, Motomi Mori
, David Soong
, Clare V. LeFave
, Fei Huang
, Homer Adams
, Marc M. Loriaux
, Cristina E. Tognon
, Pierrette Lo
, Jeffrey W. Tyner
, Guang Fan
, Shannon K. McWeeney

Brian J. Druker, Evan F. Lind

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

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.

Original language	English (US)
Pages (from-to)	14331-14341
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	25
DOIs	https://doi.org/10.1073/pnas.1916206117
State	Published - Jun 23 2020

Funding

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’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.

Funders	Funder number
Leukemia and Lymphoma Society of America Beat
National Cancer Institute Cancer Center Support
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health
National Institute of Health-National Cancer Institute	U01CA217862, P30CA069533, 1R01CA183947, U54CA224019
V Foundation for Cancer Research
Oregon State University/Oregon Health and Science University
Gabrielle's Angel Foundation for Cancer Research

Keywords

AML
Checkpoint blockade
Immune microenvironment
Leukemia
T cell

ASJC Scopus subject areas

General

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10.1073/pnas.1916206117

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Lamble, A. J., Kosaka, Y., Laderas, T., Maffit, A., Kaempf, A., Brady, L. K., Wang, W., Long, N., Saultz, J. N., Mori, M., Soong, D., LeFave, C. V., Huang, F., Adams, H., Loriaux, M. M., Tognon, C. E., Lo, P., Tyner, J. W., Fan, G., ... Lind, E. F. (2020). Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America, 117(25), 14331-14341. https://doi.org/10.1073/pnas.1916206117

Lamble, AJ, Kosaka, Y, Laderas, T, Maffit, A, Kaempf, A, Brady, LK, Wang, W, Long, N, Saultz, JN, Mori, M, Soong, D, LeFave, CV, Huang, F, Adams, H, Loriaux, MM , Tognon, CE, Lo, P, Tyner, JW , Fan, G , McWeeney, SK , Druker, BJ & Lind, EF 2020, 'Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 25, pp. 14331-14341. https://doi.org/10.1073/pnas.1916206117

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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.",

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AU - Lind, Evan F.

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Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia

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