Immune cell constitution in bone marrow microenvironment predicts outcome in adult ALL

Helena Hohtari,Riku Turkki,Satu Mustjoki,Sami Blom,Oscar Brück,Kimmo Porkka,Olli Kallioniemi,Panu E Kovanen,Teijo Pellinen,Marjatta Sinisalo

doi:10.1038/s41375-018-0360-1

Abstract

As novel immunological treatments are gaining a foothold in the treatment of acute lymphoblastic leukemia (ALL), it is elemental to examine ALL immunobiology in more detail. We used multiplexed immunohistochemistry (mIHC) to study the immune contexture in adult precursor B cell ALL bone marrow (BM). In addition, we developed a multivariate risk prediction model that stratified a poor survival group based on clinical parameters and mIHC data. We analyzed BM biopsy samples of ALL patients (n = 52) and healthy controls (n = 14) using mIHC with 30 different immunophenotype markers and computerized image analysis. In ALL BM, the proportions of M1-like macrophages, granzyme B+CD57+CD8+ T cells, and CD27+ T cells were decreased, whereas the proportions of myeloid-derived suppressor cells and M2-like macrophages were increased. Also, the expression of checkpoint molecules PD1 and CTLA4 was elevated. In the multivariate model, age, platelet count, and the proportion of PD1+TIM3+ double-positive CD4+ T cells differentiated a poor survival group. These results were validated by flow cytometry in a separate cohort (n = 31). In conclusion, the immune cell contexture in ALL BM differs from healthy controls. CD4+PD1+TIM3+ T cells were independent predictors of poor outcome in our multivariate risk model, suggesting that PD1 might serve as an attractive immuno-oncological target in B-ALL.

Highlights

Acute lymphoblastic leukemia (ALL) is a malignant disease of the early lymphoid precursors, which occurs in all age groups
We present a detailed description of immune cell constitution in adult precursor B cell ALL bone marrow (BM) microenvironment at diagnosis using multiplex immunohistochemistry and computerized image analysis (Fig. 1a)
As M2-like macrophages and myeloid-derived suppressor cells (MDSCs) are able to promote tumor growth by dampening Th1-mediated immune responses, we examined the level of immunosuppressive myeloid cells [34, 35]

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is a malignant disease of the early lymphoid precursors, which occurs in all age groups. The contemporary survival rates in children are excellent, whereas the treatment results in adults are still suboptimal and most patients die of their leukemia. Current treatment consists of multiagent chemotherapy to induce and consolidate remission, followed by prolonged maintenance therapy [1, 2]. Treatment guided by sensitive monitoring of minimal residual disease (MRD) and the introduction of pediatric-modeled regimens in younger adults have improved patient outcome [3,4,5]. Introducing tyrosine kinase inhibitors (TKIs) into treatment regimens has improved survival in Ph+ ALL [7,8,9]. In addition to direct oncokinase inhibition, TKI therapy modulates the immune system, which may play a critical role in suppressing the growth of leukemic cells [10,11,12,13,14]

Methods

Results

Conclusion