Nurse-like cells impact on disease progression in chronic lymphocytic leukemia

Boissard, Frédéric; Laurent, Césari; Ramsay, Alan G.; Quillet‐Mary, Anne; Jj, Fournié; Poupot, Mary; Ysebaert, Loïc

doi:10.1038/bcj.2015.108

Cited by 30 publications

(44 citation statements)

References 14 publications

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“…These TAMs have protean pro-survival effects including increased angiogenesis, tumor cell invasion, metastasis, and inhibition of immune-mediated anti-tumor responses [ 5 ]. TAMs have also been isolated from the peripheral blood, spleen, and lymph nodes in CLL patients where they have shown to be essential for CLL cell survival in the tumor microenvironment [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples

Edwards

Sweeney

et al. 2018

Oncotarget

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In many malignancies, the tumor microenvironment includes CSF1R-expressing supportive monocyte/macrophages that promote tumor cell survival. For chronic lymphocytic leukemia (CLL), these supportive monocyte/macrophages are known as nurse-like cells (NLCs), although the potential effectiveness of selective small-molecule inhibitors of CSF1R against CLL is understudied. Here, we demonstrate the preclinical activity of two inhibitors of CSF1R, GW-2580 and ARRY-382, in primary CLL patient samples. We observed at least 25% of CLL samples showed sub-micromolar sensitivity to CSF1R inhibitors. This sensitivity was observed in samples with varying genetic and clinical backgrounds, although higher white cell count and monocyte cell percentage was associated with increased sensitivity. Depleting CD14-expressing monocytes preferentially decreased viability in samples sensitive to CSF1R inhibitors, and treating samples with CSF1R inhibitors eliminated the presence of NLCs in long-term culture conditions. These results indicate that CSF1R small-molecule inhibitors target CD14-expressing monocytes in the CLL microenvironment, thereby depriving leukemia cells of extrinsic support signals. In addition, significant synergy was observed combining CSF1R inhibitors with idelalisib or ibrutinib, two current CLL therapies that disrupt tumor cell intrinsic B-cell receptor signaling. These findings support the concept of simultaneously targeting supportive NLCs and CLL cells and demonstrate the potential clinical utility of this combination.

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Section: Introductionmentioning

confidence: 99%

Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples

Edwards

Sweeney

et al. 2018

Oncotarget

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“…5 They sustain malignant B-cell survival 6,7 and are a major cellular component of the leukemia microenvironment in lymphoid tissues 8,9 of patients with progressive but not stable disease, suggesting that these cells have an impact on the natural history of CLL. 10,11 Type I invariant natural killer T (iNKT) cells are a conserved T-cell subset expressing a semi-invariant T-cell receptor (TCR) containing the Va14-Ja18 and Va24-Ja18 chains in mice and humans, respectively. iNKT cells react with self-or microbial-derived lipid antigens, such as a-galactosyl ceramide (a-GalCer), presented by the HLA class I-related molecule CD1d.…”

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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“…In CLL, evidence supports a "symbiotic" relationship between the malignant CLL cells and tumour associated macrophages, (Figure 2). For example, TAMs are required to maintain the survival of the malignant B cells within the bone marrow [36][37][38][39].…”

Section: The Role Of Macrophages In Cll Pathogenesismentioning

confidence: 99%

The duality of macrophage function in chronic lymphocytic leukaemia

Chen

Mapp

Blumenthal

et al. 2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia and, in some patients, is accompanied by resistance to both chemotherapeutics and immunotherapeutics. In this review we will discuss the role of tumour associated macrophages (TAMs) in promoting CLL cell survival and resistance to immunotherapeutics. In addition, we will discuss mechanisms by which TAMs suppress T-cell mediated antitumour responses. Thus, targeting macrophages could be used to i) reduce the leukaemic burden via the induction of T-cell-mediated antitumour responses, ii) to reduce pro-survival signalling and enhance response to conventional chemotherapeutics or iii) enhance the response to therapeutic antibodies in current clinical use.

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Nurse-like cells impact on disease progression in chronic lymphocytic leukemia

Cited by 30 publications

References 14 publications

Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples

Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples

Invariant NKT cells contribute to chronic lymphocytic leukemia surveillance and prognosis

The duality of macrophage function in chronic lymphocytic leukaemia

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