Risk-associated alterations in marrow T cells in pediatric leukemia.

Jithendra Kini Bailur,Hong Seo Lim,Connor Foster,Peng Qiu,Katherine Pendleton,Kavita M Dhodapkar,Melissa L Kemp,Alyssa Duffy,Deborah Deryckere,Madhav V Dhodapkar,Sharon Castellino,Samuel S Mccachren,Deon B Doxie,Akhilesh Kaushal,Juan C Vasquez

doi:10.1172/jci.insight.140179

Abstract

Current management of childhood leukemia is tailored based on disease risk determined by clinical features at presentation. Whether properties of the host immune response impact disease risk and outcome is not known. Here, we combine mass cytometry, single cell genomics, and functional studies to characterize the BM immune environment in children with B cell acute lymphoblastic leukemia and acute myelogenous leukemia at presentation. T cells in leukemia marrow demonstrate evidence of chronic immune activation and exhaustion/dysfunction, with attrition of naive T cells and TCF1+ stem-like memory T cells and accumulation of terminally differentiated effector T cells. Marrow-infiltrating NK cells also exhibit evidence of dysfunction, particularly in myeloid leukemia. Properties of immune cells identified distinct immune phenotype–based clusters correlating with disease risk in acute lymphoblastic leukemia. High-risk immune signatures were associated with expression of stem-like genes on tumor cells. These data provide a comprehensive assessment of the immune landscape of childhood leukemias and identify targets potentially amenable to therapeutic intervention. These studies also suggest that properties of the host response with depletion of naive T cells and accumulation of terminal-effector T cells may contribute to the biologic basis of disease risk. Properties of immune microenvironment identified here may also impact optimal application of immune therapies, including T cell–redirection approaches in childhood leukemia.

Highlights

Acute leukemias are a leading cause of death from cancer before age 20 in the United States [1]
CD3+ T cells as a proportion of total BM mononuclear cells (BMMNCs) were lower in the leukemic marrow relative to healthy donors (HD), as expected, due to leukemic cell infiltration (Supplemental Figure 1A)
Within the CD3+ T cell compartment, the proportion of CD4+ and CD8+ subsets was comparable between HD and patients with B cell acute lymphoblastic leukemia (B-ALL) or acute myeloid leukemia (AML) (Supplemental Figure 1B)

Summary

Introduction

Acute leukemias are a leading cause of death from cancer before age 20 in the United States [1] Both B cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML) comprise multiple entities with a distinct constellation of somatic genetic alterations, including aneuploidy, chromosome translocations, and somatic mutations [2,3,4]. Immune-based approaches such as redirection of T cells to tumors with chimeric antigen receptors (CARs) have led to impressive and durable responses in children with B-ALL [7]. It is increasingly appreciated, mostly from studies in adult cancer, that properties of the immune microenvironment are a critical determinant of outcome following immune therapies [8, 9]. Understanding the immunobiology of the tumor microenvironment will be essential for the development of effective immune therapies in childhood leukemia

Methods

Results

Conclusion