CD4⁺CD25⁺ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative

Abstract

We investigated the mechanisms of immune tolerance raised by tumors by comparing immunogenic and tolerogenic tumor cell clones isolated from a rat colon carcinoma. When injected into syngeneic hosts, the immunogenic REGb cells yield tumors that are rejected, while the tolerogenic PROb cells yield progressive tumors and inhibit the regression of REGb tumors. We show here that PROb tumor volume is correlated with an expansion of CD4 + CD25 + regulatory T lymphocytes in lymphoid tissues. These cells delay in vivo the rejection of REGb tumors and inhibit in vitro T cell-mediated immune responses against REGb cells through a mechanism that requires cell contact between effector and regulatory T cells and involves TGF-g . While total T cells from PROb tumor-bearing rats yield no apparent anti-tumor immune response, depletion of CD25 + T cells restores this reactivity. A single administration of cyclophosphamide depletes CD4 + CD25 + T cells in PROb tumor-bearing animals, delays the growth of PROb tumors, and cures rats bearing established PROb tumors when followed by an immunotherapy which has no curative effect when administered alone. These results demonstrate the role of CD4 + CD25+ regulatory T cells in tumorinduced immune tolerance and the interest of regulatory T cell depletion to sensitize established tumors to immunotherapy.

Human FOXP3 and cancer

“…In rodent models, we observed that administration of a low dose cyclophosphamide selectively decreases the number of circulating Treg in cancer-bearing animals and strongly enhances the tumor response to immunotherapy (Ghiringhelli et al, 2004;Taieb et al, 2006;Roux et al, 2008). These preclinical results were later confirmed by other investigators (Liu et al, 2007).…”

“…Experimental data obtained with rodent tumor models demonstrate that Treg reduction can dampen tumor growth and increase the efficacy of tumor immunotherapy (Ghiringhelli et al, 2004). The effects and limitation of targeting Treg in the treatment of cancer was recently reviewed (Zou, 2006;Curiel, 2008).…”

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

“…58,59 Tumor-bearing mice show an increased prevalence of Tregs not only at the tumor site but also in the peripheral blood and lymph nodes when compared with normal controls. [60][61][62] Otherwise, selective depletion of these cells may be accomplished following low-dose CTX administration. The administration of this drug at 45-day intervals block the renewal of Tregs in mice with multiple myeloma and enable the restoration of an efficient immune response against the tumor cells, thereby leading to prolonged survival and prevention of disease recurrence.…”

“…60,73,74 Paclitaxel PTX is a mitotic inhibitor that causes cell cycle arrest by stabilizing tubulin in microtubules. It is another useful agent for LDM therapy given its broad spectrum antitumor activity and ability to in vitro inhibit endothelial cell functions that are fundamental for angiogenesis.…”

Targeting and utilizing primary tumors as live vaccines: changing strategies

“…Data from both preclinical studies and clinical trails highlight that some chemotherapeutic drugs reduce regulatory T-cell (Treg) numbers, although the detailed mechanism of this action remains unknown. These drugs include cyclophosphamide (Cy), [38][39][40] fludarabine 41,42 and gemcitabine, 43 among which, Cy is the best described. In mouse models, it was reported that Cy depletes CD4 1 CD25 1 Tregs, 38 and in vitro studies revealed that Cy reduces the suppressive function of Tregs by decreasing the expression of the transcription factors GITR and FoxP3.…”