The paper “Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia” published in The Proceedings of the National Academy of Sciences (PNAS) is the School of Medicine’s Paper of the Month.
Principal investigator Evan Lind, Ph.D. (pictured above, center), is an associate professor of molecular microbiology and immunology with a joint appointment in the Department of Cell, Development and Cancer Biology. He is a member of the Knight Cancer Institute.
What did you hope to learn by doing this work?
As part of the large Beat AML study that examined the genomic landscape of over 1000 acute myeloid leukemia (AML) patients, this paper is our first report that focused on the immune system. Many cancers avoid being destroyed by the immune system by establishing a “microenvironment” that results in defective immune responses. Our research was designed with two major goals. The first was to create a comprehensive roadmap of the immune microenvironment in the bone marrow and blood of patients with AML. The second was to test the functional capability of the immune cells, specifically the T cells, which reside in the bone marrow of patients with AML. From these data, we were hoping to determine whether any observed immune defects could be reversed with immune therapy, specifically by immune checkpoint blockade (ICB). These therapies have revolutionized the treatment of many types of cancer but their utility in AML remains to be determined. Because immunotherapy is not effective in every patient, we were also hoping to provide insight on how to identify the patients that would most likely benefit from this therapy.
What did you actually learn?
Our work examined bone marrow and blood samples from over 100 patients with AML, of which we reported a subset in this paper. We learned that, like the disease itself, there is a great deal of variability in the composition and functional capacity of the immune system among patients. A little over one-third of all samples showed profound defects in T cell responses. Interestingly, however, we also found that the ICBs we tested were able to boost the function of these T cells in roughly 75% of those immune-compromised samples. This was somewhat surprising given the number and diversity of mechanisms in place that result in dampened anti-tumor immune responses.
What do these findings mean for the future?
There are many clinical trials using ICBs in AML. However, without a solid understanding of the immune system of AML patients, the majority are likely destined to show low response rates. This study represents a foundation of the basic biology that we need to understand before we can target the immune system for treatment of AML.
This work was a team effort that would not have been possible without the input of researchers across many departments at OHSU and our collaborators at Janssen Pharmaceuticals. As part of the Beat AML study, all of the samples we acquired have detailed patient information including DNA, RNA sequencing, drug sensitivity screening and clinical outcomes. This allows us to ask many more questions about how tumor intrinsic mutations interact with the immune system in AML. Our goals going forward include identifying those patients that are most likely to respond to checkpoint blockade. Furthermore, we are investigating the effects of combined therapies that will leverage all we have learned to target both the tumor cells and the immune system to develop better treatments for AML.
“I was excited by how this work exemplified a translational team that was able to bring together patients samples and data with sophisticated mechanistic studies to suggest a possible therapeutic approach to AML,” said Mary Heinricher, Ph.D., associate dean of research, OHSU School of Medicine.
Citation
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 III, Marc M. Loriaux, Cristina E. Tognon, Pierrette Lo, Jeffrey W. Tyner, Guang Fan, Shannon K. McWeeney, Brian J. Druker, and Evan F. Lind, PNAS June 23, 2020 117 (25) 14331-14341; first published June 8, 2020 https://doi.org/10.1073/pnas.1916206117
Funding
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.
Pictured above, left to right, top to bottom: Pierrette Lo, Shannon McWeeney, Adam Lamble, Andy Kaempf, Jeffery Tyner, Nicola Long Jennifer Saultz, Evan Lind, Yoko Kosaka, Ted Laderas, Guang Fan, Brian Druker, Wei Wei Wang, Allie Maffit, Christina Tognon, Marc Loriaux.
