Minor Histocompatibility Antigen T Cell Targeting in Acute Myeloid Leukemia

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Project Summary/Abstract Acute Myeloid Leukemia (AML) is a prevalent and deadly cancer, with a predicted 20,000 new cases and 11,000 deaths from AML this year in the US. A common treatment for AML is allogeneic stem cell transplantation (alloSCT). Though potentially curative, approximately half of all patients that receive alloSCT eventually relapse and die of their disease. In alloSCT, a patient’s immune system is suppressed and bone marrow hematopoiesis ablated then reconstituted with donor hematopoietic stem cells and leukocytes. Donor T cells are able to recognize peptides derived from recipient genetic polymorphisms as foreign and destroy the cells presenting them. These peptides that differ between donor and recipient are called minor histocompatibility antigens (mHAs). If mHAs are presented on AML cells, donor T cells will kill the AML cells in what is called the graft versus leukemia (GvL) effect. However, donor T cells also target peptides presented on healthy recipient tissues causing a life-threatening side effect called graft versus host disease (GvHD). Separating GvL from GvHD is a pivotal problem in alloSCT biology. T cell targeting of mHAs that are derived from proteins only expressed in the blood is viewed as a way to augment GvL without boosting GvHD. We hypothesize that mHAs mismatched between donor and recipient are a key determinant of alloSCT outcome for AML. In this work, I investigate mHA targeting in alloSCT for AML from two perspectives: mHA and T cell. My work will elucidate the role of mHAs in alloSCT, enrich clinical assessment of AML prognosis, and identify new mHAs for future therapeutic targeting. The training in computational and wet lab immunology included here will forward my goal of becoming an independently funded physician-scientist leading a research lab in leukemia immunobiology and caring for leukemia patients. We have computationally predicted mHAs using a large dataset of over 3000 alloSCT patients. In our mHA- focused Aim 1, I will validate our predicted mHAs using mass spectrometry to identify whether they are presented on the cell surface of AML cell lines and therefore can serve as targets for T cells. Using the mHAs I validate, I will statistically define peptide features that predict presentation on the cell surface by HLA, informing future mHA identification work. I will also assess associations between validated mHAs and clinical outcome after alloSCT. I will analyze mHAs by population frequency in all ethnic groups within the US, with the goal of identifying a minimal set of mHAs that cover the majority of AML patients of all ethnicities. In our T cell-focused Aim 2, we will assess whether T cells specific for mHAs are exhausted in patients experiencing relapse after alloSCT. We predict that efficacy of these T cells predict success of alloSCT, and that exhaustion of these cells will accompany relapse. We will investigate presentation of exhaustion markers and release of proinflammatory cytokines from mHA-specific T cells from alloSCT patients before and after relapse.