CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative.
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 syngeneichosts, 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-beta. While total T cells fromPROb 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 tumor-induced immune tolerance and the interest of regulatory T cell depletion to sensitize established tumors to immunotherapy.
Ghiringhelli
François
F
INSERM U517, Faculty of Medicine, Dijon, France.
Larmonier
Nicolas
N
Schmitt
Elise
E
Parcellier
Arnaud
A
Cathelin
Dominique
D
Garrido
Carmen
C
Chauffert
Bruno
B
Solary
Eric
E
Bonnotte
Bernard
B
Martin
François
F
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy*; D003520:Cyclophosphamide / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*
D018906:Antineoplastic Agents, Alkylating; D015704:CD4 Antigens; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma; D003520:Cyclophosphamide