Chronic lymphocytic leukaemia cells become both activated and immunosuppressive following interaction with CD3 and CD28 stimulated PBMC

Hock, Barry D.; MacPherson, Sean A.; Fernyhough, Liam; McKenzie, Judith L.

doi:10.1016/j.leukres.2014.06.004

Cited by 3 publications

(13 citation statements)

References 36 publications

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“…Untreated CLL patients with white cell counts >30, were recruited through the Haematology Department, Christchurch Hospital. Peripheral blood mononuclear cells (PBMC) were prepared from normal donor blood for use as responders in functional assays and were labelled with carboxyfluorescein succinimidyl ester (CFSE) as previously described [8, 26]. For some experiments CFSE labelled PBMC were depleted of monocytes using CD14 mAb and immuno-magnetic Dynabeads [26].…”

Section: Methodsmentioning

confidence: 99%

“…If required, CLL cells were enriched from the patient PBMC by negative selection using magnetic beads as described previously [8]. All CLL preparations contained >95% CLL cells (CD19 + , CD5 + ).…”

Section: Methodsmentioning

confidence: 99%

“…CLL cells were activated as previously described [8]. Briefly, CLL cells were cultured with normal donor PBMC in the presence of CD3/CD28 antibodies for 3 days, and the CLL Act purified using CD19 positive selection.…”

Section: Methodsmentioning

confidence: 99%

“…T-cells are central to the development of effective immune responses and studies on both the T cells circulating in CLL patients and those present in CLL-T cell co-cultures provide strong evidence that CLL cells can impair T cell function [2–8]. Understanding the mechanisms underlying this process is a key step in developing new therapies that can reduce immune dysfunction and thereby improve anti-tumor responses [2, 3].…”

Section: Introductionmentioning

confidence: 99%

“…We have previously utilised a CLL + activated T cell co-culture system as an in vitro model of the pseudo follicles of the TME and demonstrated that the activated CLL cells generated are capable of suppressing polyclonal T cell responses [8, 25]. The pathways by which these activated CLL induce suppression are currently unknown and are investigated in this study using a range of agonists and antagonists that target potential pathways.…”

Section: Introductionmentioning

confidence: 99%

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Idelalisib and caffeine reduce suppression of T cell responses mediated by activated chronic lymphocytic leukemia cells

2017

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Chronic lymphocytic leukemia (CLL) is associated with T cell dysfunction. Activated CLL cells are found within the lymphoid tumor micro-environment and overcoming immuno-suppression induced by these cells may improve anti-CLL immune responses. However, the mechanisms by which activated CLL cells inhibit T cell responses, and reagents targeting such mechanisms have not been identified. Here we demonstrate that the ability of in vitro activated CLL cells to suppress T cell proliferation is not reversed by the presence of ecto-nuclease inhibitors or blockade of IL-10, PD-1 and CTLA-4 pathways. Caffeine is both an adenosine receptor antagonist and a phosphatidylinositol-3-kinase, p110δ (PI3Kδ) inhibitor and, at physiologically relevant levels, significantly reversed suppression. Significant reversal of suppression was also observed with the PI3Kδ specific inhibitor Idelalisib but not with adenosine receptor specific antagonists. Furthermore, addition of caffeine or Idelalisib to activated CLL cells significantly inhibited phosphorylation of AKT, a downstream kinase of PI3K, but did not affect CLL viability. These results suggest that caffeine, in common with Idelalisib, reduces the immuno-suppressive activity of activated CLL cells by inhibiting PI3Kδ. These findings raise the possibility that these compounds may provide a useful therapeutic adjunct by reducing immuno-suppression within the tumor micro-environment of CLL.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Idelalisib and caffeine reduce suppression of T cell responses mediated by activated chronic lymphocytic leukemia cells

2017

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The passive–aggressive relationship between CLL-B cells and T cell immunity

Davis

Ritchie

2014

Leukemia Research

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Plasma matrix metalloprotease 9 correlates with blood lymphocytosis, leukemic cell invasiveness, and prognosis in B-cell chronic lymphocytic leukemia

et al. 2017

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The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4-99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5-13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value.

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Chronic lymphocytic leukaemia cells become both activated and immunosuppressive following interaction with CD3 and CD28 stimulated PBMC

Cited by 3 publications

References 36 publications

Idelalisib and caffeine reduce suppression of T cell responses mediated by activated chronic lymphocytic leukemia cells

Idelalisib and caffeine reduce suppression of T cell responses mediated by activated chronic lymphocytic leukemia cells

The passive–aggressive relationship between CLL-B cells and T cell immunity

Plasma matrix metalloprotease 9 correlates with blood lymphocytosis, leukemic cell invasiveness, and prognosis in B-cell chronic lymphocytic leukemia

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