The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells.
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.
Galustian
Christine
C
Department of Oncology, St Georges University of London, Cranmer Terrace, Tooting, London, UK. cgalusti@sgul.ac.uk
Meyer
Brendan
B
Labarthe
Marie-Christine
MC
Dredge
Keith
K
Klaschka
Deborah
D
Henry
Jake
J
Todryk
Stephen
S
Chen
Roger
R
Muller
George
G
Stirling
David
D
Schafer
Peter
P
Bartlett
J Blake
JB
Dalgleish
Angus G
AG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D000077269:Lenalidomide; D051379:Mice; D008807:Mice, Inbred BALB C; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000970:Antineoplastic Agents; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007166:Immunosuppressive Agents; D017475:Receptors, Nerve Growth Factor; D053262:Receptors, OX40; D018125:Receptors, Transforming Growth Factor beta; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; C505716:TNFRSF4 protein, human; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D013792:Thalidomide; C467566:pomalidomide; D000077269:Lenalidomide