Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia

Sopper, Sieghart; Mustjoki, Satu; White, Deborah L.; Hughes, Timothy P.; Valent, Peter; Burchert, Andreas; Gjertsen, Bjørn Tore; Gastl, Guenther; Baldauf, Matthias; Trajanoski, Zlatko; Giles, Frank; Hochhaus, Andreas; Ernst, Thomas; Schenk, Thomas; Janssen, Jeroen; Ossenkoppele, Gert J.; Porkka, Kimmo; Wolf, Dominik

doi:10.1200/jco.2016.67.0893

Cited by 32 publications

(25 citation statements)

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“…Sopper et al (57) have reported decreased CD62L surface expression on T cells in CML patients at diagnosis. Another mechanism of impaired immune response in CML may involve aberrant PD-1/PD-L1 signaling on effector cells, and immunosuppressive Treg, which also express PD-1.…”

Section: Effector Cells Of the Immune System In CML Patients At Diagnmentioning

confidence: 99%

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

2017

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Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important in mediating TFR success. However, a major goal remains in CML to identify the most effective pathways to target to maximize an advantageous immune response and promote TFR success.

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Section: Effector Cells Of the Immune System In CML Patients At Diagnmentioning

confidence: 99%

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

2017

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“…peripheral blood (PB) of CML patients [7,8]. In addition, high CD62L+ T cells and low sCD62L+ have been suggested to predict optimal treatment response to nilotinib [9]. Although it is difficult to prove the direct causal relationship of the immune system and therapy response in patients, data from TKI discontinuation studies suggest that immune response is one of the important biological factors in successful treatment-free remission (TFR) [1,[10][11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML

et al. 2018

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Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients' CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+TIM3-CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.

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“…Previous works have demonstrated that the transendothelial migration of lymphocytes in CLL is accompanied by a downregulation of L‐selectin on circulating B‐CLL cells and it was also demonstrated that low L‐selectin expression on these cells is a negative prognostic factor . In a recent publication , it was also found, that L‐selectin levels on T‐lymphocytes in chronic myeloid leukemia patients are associated with the success of treatment, that is, low surface L‐selectin on T‐cells and elevated soluble L‐selectin levels were found to be an unfavorable sign for tyrosine kinase inhibitor treatment.…”

Section: Discussionmentioning

confidence: 96%

L‐Selectin Expression is Influenced by Phosphatase Activity in Chronic Lymphocytic Leukemia

Debreceni

Szász

Kónya

et al. 2019

Cytometry Part B Clinical

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Background Adhesion receptors have important role in cellular invasiveness and L‐selectin is a primary determinant in the binding of chronic lymphocytic leukemia (CLL) cells to several glycated proteins on endothelial cells. We investigated L‐selectin expression on CLL cells and explored the mechanisms that lead to their shedding. Methods Surface and soluble L‐selectin expression levels were studied by flow cytometry and immunoassay, respectively. Magnetically isolated B‐cells from patients and controls were investigated for total and protein phosphatase‐2A activities. Flow cytometry of permeabilized cells was utilized for the determination of phosphorylated mitogen‐activated protein kinase (pp38MAPK) and surface tumor necrosis factor alpha‐converting enzyme expression (TACE). Results In CLL patients elevated absolute lymphocyte cell counts, high soluble and low surface L‐selectin expression were observed. Similarly, TACE surface expression was significantly lower on B‐CLL cells compared to normal B‐cells. Both total phosphatase and protein phosphatase‐2A activities were also significantly lower in B‐CLL cells compared to normal B‐cells and we found a consequently higher level of pp38 MAPK in B‐CLL cells. Based on in vitro experiments a MAPK inhibitor could attenuate the phosphatase inhibitor's effect on L‐selectin shedding. Conclusions The lower phosphatase activity detectable in chronic lymphocytic leukemia, results in a downstream signaling cascade with subsequent reduction of surface L‐selectin expression and this effect is mediated by enhanced phosphorylation of p38MAPK and an altered TACE expression. © 2019 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.

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Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia

Cited by 32 publications

References 42 publications

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML

L‐Selectin Expression is Influenced by Phosphatase Activity in Chronic Lymphocytic Leukemia

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