Acute myeloid leukemias (AML) are a group of cancers of the myeloid line of blood cells that arise out of the bone marrow, progress rapidly, and interfere with the production of normal immune cells. Most AML patients who achieve a remission with standard cytotoxic chemotherapy will go on to relapse, after which there are very few treatment options. Inhibition of the PD-1/PD-L1 axis has shown remarkable efficacy in patients with solid tumors, and immune checkpoint inhibition (ICI) is now being explored as an immunotherapeutic option to treat AML relapse. In this dissertation, I hypothesized that T cells in AML patients who have been treated with chemotherapy can be stimulated by ICI. Specifically, through a series of discrete aims, I provide detailed characterizations of (1) residual adaptive immunity in AML patients who have been treated with standard induction and consolidation chemotherapy to induce remission, (2) inhibitory receptors expressed by T cells residing in the BM of relapsed/refractory AML (R-AML), (3) T cell dynamics in R-AML patients treated with the anti-PD-1 immune checkpoint inhibitor pembrolizumab, and finally, (4) T cell clonotypes that may have contributed to the development of an immune-related adverse event (irAE). In Chapters 3 and 4, I identify impaired B cell immunity and normal phenotype and functionality of the T cell compartment in AML patients in a first remission, as well as a striking preservation of BM T cell phenotype in R-AML patients when compared to a cohort of age matched healthy donors (HD). These results show that T cells in AML patients after chemotherapy are capable of mounting immune responses. In Chapter 5, I evaluate changes induced in the frequency of T cell clones in R-AML patients treated with pembrolizumab and identify significantly expanded T cell clones whose expansion coincides with the development of autoimmunity in patients who developed irAEs during treatment. To better study these expanded clones and to link TCR with gene expression and phenotype, I optimized and implemented a single cell RNA sequencing (scRNA-seq) workflow, providing an unparalleled view of T cell biology at the single cell level. I employed this scRNA-seq strategy on a R-AML patient who developed pembrolizumab-induced hypothyroidism and show that T cell clonotypes that expanded at irAE onset were of an effector memory phenotype with high cell surface PD-1 expression with a transcriptional profile suggestive of activation, proliferation, and degranulation. Summarily, the work in this dissertation offers strong evidence that AML patients at various clinical stages of disease who have been treated with cytotoxic chemotherapies retain a functional T cell adaptive immune compartment and that treatment with an anti-PD-1 immune checkpoint inhibitor can stimulate T cells in R-AML.
|Advisor:||Hourigan, Christopher, Lee, Norman|
|Commitee:||Boritz, Eli, Chiappinelli, Katherine, Villagra, Alejandro, Barrett, John|
|School:||The George Washington University|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 81/11(E), Dissertation Abstracts International|
|Keywords:||AML, B cell, Immunotherapy, irAE, PD-1, T cell|
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