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

Cancer Immunol Immunother. 2009 Jul;58(7):1033-45. doi: 10.1007/s00262-008-0620-4. Epub 2008 Nov 14.


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-alpha 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-dependent 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-beta 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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / metabolism
  • Female
  • Forkhead Transcription Factors / antagonists & inhibitors
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism*
  • Glucocorticoid-Induced TNFR-Related Protein
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Lenalidomide
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Nerve Growth Factor / drug effects
  • Receptors, Nerve Growth Factor / immunology
  • Receptors, Nerve Growth Factor / metabolism
  • Receptors, OX40 / antagonists & inhibitors
  • Receptors, OX40 / immunology
  • Receptors, OX40 / metabolism
  • Receptors, Transforming Growth Factor beta / drug effects
  • Receptors, Transforming Growth Factor beta / immunology
  • Receptors, Transforming Growth Factor beta / metabolism
  • Receptors, Tumor Necrosis Factor / drug effects
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Thalidomide / analogs & derivatives*
  • Thalidomide / pharmacology
  • Transforming Growth Factor beta / drug effects
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism


  • Antineoplastic Agents
  • Forkhead Transcription Factors
  • Glucocorticoid-Induced TNFR-Related Protein
  • Immunosuppressive Agents
  • Receptors, Nerve Growth Factor
  • Receptors, OX40
  • Receptors, Transforming Growth Factor beta
  • Receptors, Tumor Necrosis Factor
  • TNFRSF18 protein, human
  • TNFRSF4 protein, human
  • Transforming Growth Factor beta
  • Interleukin-10
  • Thalidomide
  • pomalidomide
  • Lenalidomide