Abstract
BackgroundTumor cells have evolved complex strategies to escape immune surveillance, a process which involves NK cells and T lymphocytes, and various immunological factors. Indeed, tumor cells recruit immunosuppressive cells [including regulatory T-cells (Treg), myeloid-derived suppressor cells (MDSC)] and express factors such as PD-L1. Molecularly targeted therapies, such as imatinib, have off-target effects that may influence immune function. Imatinib has been shown to modulate multiple cell types involved in anti-cancer immune surveillance, with potentially detrimental or favorable outcomes. Imatinib and other tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) have dramatically changed disease course. Our study aimed to characterize the different populations of the immune system in patients with CML affected by their treatment.MethodsForty-one patients with CML [33 treated with TKIs and 8 with TKIs plus interferon (IFN)-α] and 20 controls were enrolled in the present study. Peripheral blood populations of the immune system [referred to as the overview of immune system (OVIS) panel, Treg cells and MDSCs] and PD-1 expression were evaluated by flow cytometry. The immunological profile was assessed using the mRNA Pan-Cancer Immune Profiling Panel and a NanoString nCounter FLEX platform.ResultsPatients receiving combination therapy (TKIs + IFN-α) had lower numbers of lymphocytes, particularly T cells [838/µL (95% CI 594–1182)] compared with healthy controls [1500/µL (95% CI 1207 – 1865), p = 0.017]. These patients also had a higher percentage of Treg (9.1%) and CD4+PD-1+ cells (1.65%) compared with controls [Treg (6.1%) and CD4+/PD-1+(0.8%); p ≤ 0.05]. Moreover, patients treated with TKIs had more Mo-MDSCs (12.7%) whereas those treated with TKIs + IFN-α had more Gr-MDSC (21.3%) compared to controls [Mo-MDSC (11.4%) and Gr-MDSC (8.48%); p ≤ 0.05]. CD56bright NK cells, a cell subset endowed with immune-regulatory properties, were increased in patients receiving TKIs plus IFN-α compared with those treated with TKIs alone. Interestingly, serum IL-21 was significantly lower in the TKIs plus IFN-α cohort. Within the group of patients treated with TKI monotherapy, we observed that individuals receiving 2nd generation TKIs had lower percentages of CD4+ Treg (3.63%) and Gr-MDSC (4.2%) compared to patients under imatinib treatment (CD4+ Treg 6.18% and Gr-MDSC 8.2%), but higher levels of PD-1-co-expressing CD4+ cells (1.92%).ConclusionsOur results suggest that TKIs in combination with IFN-α may promote an enhanced immune suppressive state.
Highlights
Tumor cells have evolved complex strategies to escape immune surveillance, a process which involves natural killer (NK) cells and T lymphocytes, and various immunological factors
The overview of immune system (OVIS) analysis highlights differences between treatment groups In order to evaluate whether treatment with tyrosine kinase inhibitors (TKIs), either alone or in combination with IFN-α, had an impact on immune cell populations in patients with chronic myeloid leukemia (CML), we initially assessed the frequency and absolute numbers of leukocyte subsets and immune cell populations using the Overall Immune System (OVIS) antibody panel (Additional file 1 and Table 2) [25]
The degree of peripheral lymphopenia was higher in CML patients receiving TKIs plus IFN-α [1140/μL of blood] compared with individuals receiving TKIs only [1853/μL; Table 2 Overview of immune system (OVIS)
Summary
Tumor cells have evolved complex strategies to escape immune surveillance, a process which involves NK cells and T lymphocytes, and various immunological factors. Tumor cells recruit immunosuppressive cells [including regulatory T-cells (Treg), myeloid-derived suppressor cells (MDSC)] and express factors such as PD-L1. Targeted therapies, such as imatinib, have off-target effects that may influence immune function. Imatinib and other tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) have dramatically changed disease course. Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of the oncogenic BCR-ABL1 fusion gene derived from the reciprocal translocation of the long arms of chromosome 9 and chromosome 22 [1]. The upfront administration of TKIs and IFN-α, followed by low-dose IFN-α maintenance, enabled a high rate of imatinib discontinuation in CML patients in major molecular response (MMR) [6]
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