Functional invariant natural killer T-cell and CD1d axis in chronic lymphocytic leukemia: implications for immunotherapy

Weinkove, Robert; Brooks, Collin; Carter, John M.; Hermans, Ian F.; Ronchese, Franca

doi:10.3324/haematol.2012.072835

Cited by 35 publications

(39 citation statements)

References 49 publications

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“…It is important to note that iNKT cells have recently been revealed as a one of key players in the immune responses against tumors [34] and their numbers and function were found to be normal in patients with CLL in early stages [35]. Our results suggest that that progression of CLL is associated with downregulation of Th17 cells and expansion of Treg cells.…”

Section: Discussionmentioning

confidence: 52%

Th17/IL-17A Might Play a Protective Role in Chronic Lymphocytic Leukemia Immunity

et al. 2013

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Th17 cells, a recently discovered subset of T helper cells that secrete IL-17A, can affect the inflammation process autoimmune and cancer diseases development. The purpose of this study was to evaluate the role of Th17 cells and IL17A in biology of CLL. The study group included 294 untreated CLL patients in different clinical stages. Here, we show that higher Th17 and IL-17A values were associated with less advanced clinical stage of CLL. Th17 cells’ percentages in PB were lower in patients who died due to CLL during follow-up due to CLL (as compared to surviving patients) and in patients responding to first-line therapy with fludarabine-based regimens (as compared to non-responders). IL-17A inversely correlated with the time from CLL diagnosis to the start of therapy and was lower in patients who required treatment during follow-up. Th-17 and IL-17A values were lower in patients with adverse prognostic factors (17p and 11q deletion, CD38 and ZAP-70 expression). CLL patients with detectable IL-17A mRNA in T cells were in Rai Stage 0 and negative for both ZAP-70 and CD38 expression. Th17 percentages positively correlated with iNKT and adversely with Treg cells. The results of this study suggest that Th17 may play a beneficial role in CLL immunity.

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Section: Discussionmentioning

confidence: 52%

Th17/IL-17A Might Play a Protective Role in Chronic Lymphocytic Leukemia Immunity

et al. 2013

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“…iNKT cells that we have recently reported [5]. Knowing that several tumours use CD1d downregulation to evade immune detection [9][10][11][12], we examined whether cell surface CD1d was modified in CML-CP mDCs.…”

Section: In Vitro Differentiation Of Mature Mdcs From Blood Monocytesmentioning

confidence: 99%

The Rho–ROCK pathway as a new pathological mechanism of innate immune subversion in chronic myeloid leukaemia

Basbous

Levescot

Piccirilli

et al. 2016

The Journal of Pathology

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CD1d-restricted invariant natural killer T (iNKT) cells are believed to play a key role in cancer immune surveillance, and are functionally deficient in patients with chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker. On the other hand, reduced membrane expression was not associated with decreased intracytoplasmic levels of CD1d or its mRNA transcripts, consistent with intracellular retention. In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. An inhibitor of BCR-ABL tyrosine kinase (TK), imatinib mesylate (IM), had no such activity. Similar recovery of CD1d expression occurred with fasudil, another ROCK inhibitor that is commonly used in clinical trials. Our data support the conclusion that BCR-ABL-dependent ROCK, but not TK, is involved in CD1d downregulation. We propose that ROCK, which is most likely activated by the DH/PH domain of BCR-ABL, mediates iNKT-cell immune subversion in CML patients by downregulating CD1d expression on CML mDCs. Our study reveals the ROCK-mDC axis as a new potential target to restore immune surveillance in patients with CML, offering new therapeutic perspectives for CML treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…[19][20][21] In CLL patients, it was reported that CD1d expression by malignant cells correlates with adverse prognosis, whereas iNKT cells can recognize leukemia cells in vitro when preloaded with synthetic a-GalCer. [22][23][24] However, the role of iNKT cells in the natural history of CLL is essentially unknown.…”

Section: Introductionmentioning

confidence: 99%

Invariant NKT cells contribute to chronic lymphocytic leukemia surveillance and prognosis

Gorini

Azzimonti

Delfanti

et al. 2017

Blood

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Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant CD5 B lymphocytes in blood, bone marrow, and lymphoid organs. CD1d-restricted invariant natural killer T (iNKT) cells are innate-like T lymphocytes strongly implicated in tumor surveillance. We investigated the impact of iNKT cells in the natural history of the disease in the Eμ-Tcl1 (Tcl1) CLL mouse model and 68 CLL patients. We found that Tcl1-CLL cells express CD1d and that iNKT cells critically delay disease onset but become functionally impaired upon disease progression. In patients, disease progression correlates with high CD1d expression on CLL cells and impaired iNKT cells. Conversely, disease stability correlates with negative or low CD1d expression on CLL cells and normal iNKT cells, suggesting indirect leukemia control. iNKT cells indeed hinder CLL survival in vitro by restraining CD1d-expressing nurse-like cells, a relevant proleukemia macrophage population. Multivariable analysis identified iNKT cell frequency as an independent predictor of disease progression. Together, these results support the contribution of iNKT cells to CLL immune surveillance and highlight iNKT cell frequency as a prognostic marker for disease progression.

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Functional invariant natural killer T-cell and CD1d axis in chronic lymphocytic leukemia: implications for immunotherapy

Cited by 35 publications

References 49 publications

Th17/IL-17A Might Play a Protective Role in Chronic Lymphocytic Leukemia Immunity

Th17/IL-17A Might Play a Protective Role in Chronic Lymphocytic Leukemia Immunity

The Rho–ROCK pathway as a new pathological mechanism of innate immune subversion in chronic myeloid leukaemia

Invariant NKT cells contribute to chronic lymphocytic leukemia surveillance and prognosis

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