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The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells

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Abstract

Lenalidomide (Revlimid®; CC-5013) and pomalidomide (CC-4047) are IMiDs® proprietary drugs having immunomodulatory properties that have both shown activity in cancer clinical trials; lenalidomide is approved in the United States for a subset of MDS patients and for treatment of patients with multiple myeloma when used in combination with dexamethasone. These drugs exhibit a range of interesting clinical properties, including anti-angiogenic, anti-proliferative, and pro-erythropoietic activities although exact cellular target(s) remain unclear. Also, anti-inflammatory effects on LPS-stimulated monocytes (TNF-α is decreased) and costimulatory effects on anti-CD3 stimulated T cells, (enhanced T cell proliferation and proinflammatory cytokine production) are observed These drugs also cause augmentation of NK-cell cytotoxic activity against tumour-cell targets. Having shown that pomalidomide confers T cell-dependant adjuvant-like protection in a preclinical whole tumour-cell vaccine-model, we now show that lenalidomide and pomalidomide strongly inhibit T-regulatory cell proliferation and suppressor-function. Both drugs inhibit IL-2-mediated generation of FOXP3 positive CTLA-4 positive CD25high CD4+ T regulatory cells from PBMCs by upto 50%. Furthermore, suppressor function of pre-treated T regulatory cells against autologous responder-cells is abolished or markedly inhibited without drug related cytotoxicity. Also, Balb/C mice exhibit 25% reduction of lymph-node T regulatory cells after pomalidomide treatment. Inhibition of T regulatory cell function was not due to changes in TGF-β or IL-10 production but was associated with decreased T regulatory cell FOXP3 expression. In conclusion, our data provide one explanation for adjuvant properties of lenalidomide and pomalidomide and suggest that they may help overcome an important barrier to tumour-specific immunity in cancer patients.

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  1. Keith Dredge

    Present address: Progen Industries, Ipswich Road, Brisbane, QLD, 2806, Australia

Authors and Affiliations

  1. Department of Oncology, St Georges University of London, Cranmer Terrace, Tooting, London, UK

    Christine Galustian, Brendan Meyer, Marie-Christine Labarthe, Keith Dredge, Deborah Klaschka, Jake Henry & Angus G. Dalgleish

  2. Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

    Stephen Todryk

  3. Celgene Corporation, 86 Morris Avenue, Summit, NJ, 07901, USA

    Roger Chen, George Muller, David Stirling, Peter Schafer & J. Blake Bartlett

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Marie-Christine Labarthe and Keith Dredge contributed equally to this paper.

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Galustian, C., Meyer, B., Labarthe, MC. et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother 58, 1033–1045 (2009). https://doi.org/10.1007/s00262-008-0620-4

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