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Tumor-derived IL-6 may contribute to the immunological defect in CLL

Leukemia volume 22, pages 1084–1087 (2008)Cite this article

Chronic lymphocytic leukemia (CLL) is an indolent disorder with a highly variable course whose clinical features arise through the accumulation of tumor cells in the bone marrow, blood and secondary lymphoid tissue. While hematopoietic failure may occur in those with advanced disease, for the majority it is immune dysfunction, manifested as susceptibility to infection or autoimmunity, which dominates the clinical picture. Both the disease and its treatment may affect the number of normal cells in the innate and adaptive immune systems, however, it is clear that there are also more subtle qualitative defects which presumably arise either through contact with the expanded neoplastic B cell compartment or because of the secretion of immunomodulatory cytokines. A variety of functional defects in T cells from patients with CLL have been reported including, reduction in activation-induced CD40L expression1 and abnormalities of gene expression affecting the differentiation of CD4 cells and cytoskeletal function and vesicle transport in CD8 cells.2 Although these abnormalities were shown to arise through contact with the malignant clone it is clear that soluble mediators may also play a role, as we have previously shown in myeloid malignancies.3 In the present study, we sought to characterize and identify soluble immunomodulatory factors in CLL since these might lend themselves to therapeutic intervention.

In addition to its effect on activation-induced expression of CD40L, TSN from all 17 CLL cases also inhibited IL-2 production by normal T cells. The effects of TSN on CD40L level and IL-2 secretion varied from patient to patient and were broadly correlated (Figure 2b, P=0.008, r2=0.52), suggesting involvement of the same factor(s). Inhibition of CD40L expression by TSN also paralleled its inhibitory effects on the allogeneic MLR as a significant correlation was observed between the inhibition of CD40L expression after 24 h and [3H]thymidine incorporation at 5 days in an MLR (P=0.0002, r2=0.56, n=9). CLL cells thus secrete soluble mediator(s) that inhibit both the activation and proliferation of normal T cells. Since these results were at variance with a previous report suggesting that cell contact and not soluble factors mediate the CD40L abnormality in CLL,1 we investigated the mechanism of this defect. While contact with CLL cells caused downregulation of CD40L by T cells that had been previously activated, TSN inhibited upregulation during T cell activation. The CD40L defect in CLL patients could be reversed by purification of T cells and removal of contact with tumor cells and their secreted factors proving that there is no intrinsic abnormality of this system in CLL T cells.

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Acknowledgements

Supported by grants from the Leukaemia Research Fund, Gretna charitable trust and an unrestricted educational grant from Chugai Pharma.

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  1. Department of Haematological Medicine, King's College London, London, UK

    A G S Buggins, P E M Patten, J Richards, N S B Thomas, G J Mufti & S Devereux

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  1. A G S Buggins
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  2. P E M Patten
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  3. J Richards
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  4. N S B Thomas
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  6. S Devereux
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Correspondence to A G S Buggins.

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Buggins, A., Patten, P., Richards, J. et al. Tumor-derived IL-6 may contribute to the immunological defect in CLL. Leukemia 22, 1084–1087 (2008). https://doi.org/10.1038/sj.leu.2405015

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