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

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.

Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

“…[11][12][13][14] However, unlike in solid tumors, the clinical efficacy of immune checkpoint inhibition, particularly PD-1 inhibitor monotherapy, appears to be limited in AML, MDS, and multiple myeloma (MM), [15][16][17][18] which may be due to the complexity of the leukemic bone marrow (BM) microenvironment in which persistent stimulation of leukemia cell-derived antigen results in more complex T-cell exhaustion and dysfunction. [19][20][21] In this case, more than one immune inhibitory receptor may contribute to T-cell dysfunction. The heterogeneity of exhausted T cells may be a reason for the lower effects of PD-1 inhibitors.…”

The bone marrow microenvironment of pre-B acute lymphoblastic leukemia at single-cell resolution

“…Understanding the tumor microenvironment can lead to identification of novel therapeutic targets. Previous studies have shown that development of B-ALL alters immune cell constitution and the BMM 9,[28][29][30] . In this study, we dissected responses of normal bone marrow immune cells during early stages of B-cell leukemia development at a single-cell level.…”

Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies

“…Co-culturing M2-macrophages with T-ALL cell in vitro significantly induced leukemic cell proliferation via C5a, TNFα, growth-related oncogene (GRO)-α and IL-6 [22]. Hohtari et al analyzed immune cell constitution in adult precursor B cell ALL bone marrow (BM), demonstrating increased proportion of M2-like macrophages and myeloid-derived suppressor cells (MDSCs) in ALL patients' BM compared to healthy patients [23].…”