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

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-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.

Treatment with lenalidomide induces immunoactivating and counter-regulatory immunosuppressive changes in myeloma patients

“…Others report the development of severe acute GvHD in lenalidomide-treated, allo-SCtransplanted patients, despite high levels of Tregs in the peripheral blood [43], indicating that Tregs may not always be capable of neutralizing the immunostimulatory effects of lenalidomide. Furthermore, lenalidomide has been shown to inhibit the proliferation and function of Tregs in vitro [44], possibly explaining the occasionally observed incapacity of Tregs to inhibit T cell-mediated immunity.…”

T-regulatory cell modulation: the future of cancer immunotherapy?

“…A recent in vitro study showed the ability of lenalidomide (Revlimid, Celgene Corporation, Summit, NJ, USA; CC-5013) and CC-4047 to suppress Treg function and proliferation; effects that may be mediated by downregulation of FOXP3 (Galustian et al, 2008). Both drugs are active against multiple myeloma, and it is tempting to speculate that this is mediated by their anti-Treg properties, although co-stimulatory and anti-angiogenic activity have also been shown.…”

Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients

“…17,19,20 Lenalidomide's mode of action in MDS is not well understood, but its proposed biological effects include inhibition of angiogenesis, promotion of erythroid hemoglobin production and acceleration of apoptotic death of abnormal hematopoietic progenitors, 16,17,21 and it is also reported to have immunoregulatory activity through modulation of natural killer cell, monocyte and dendritic cell function, inhibition of FOXP3 þ T regulatory cells and costimulation of T cells leading to increased proliferation and interferon-g (IFN-g) production. 16,[22][23][24] Interestingly, many of these immunological activities have been attributed in other settings to the prodigious cytokine production of NKT cells. [2][3][4]25 A causative link has not been established between NKT cell defects and the development of MDS, but disordered NKT cell function has been reported for patients with MDS, [10][11][12] and is clearly implicated in the control or progression of a wide range of tumors.…”