Submitted June 4, 2008
Accepted February 19, 2009
Role of GM-CSF signaling in cell-based tumor immunization
Shohreh Zarei, Frank Schwenter, Patricia Luy, Michel Aurrand-Lions, Philippe Morel, Manfred Kopf, Glenn Dranoff, and Nicolas Mach*
Oncology Division, Department of Internal Medicine, Geneva University Hospital and Geneva Medical School, Geneva, Switzerland
Visceral and Transplantation Unit, Department of Surgery, Geneva University Hospital and Geneva Medical School, Geneva, Switzerland
Paoli-Calmettes Institute, Inserm, Cancer Research Center, Marseille, France
Department of Environmental Science, Swiss Federal Institute of Technology, Zurich, Switzerland
Department of Adult Oncology, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, United States
* Corresponding author; email: nicolas.mach{at}medecine.unige.ch.
GM-CSF is a potent adjuvant in cancer vaccination; however specific role of endogenous GM-CSF remains unknown. To address this question, we performed cell-based vaccination in two tumor models. First, we vaccinated C57BL/6 mice lacking either GM-CSF, IL-5 or beta-common chain (
c), a receptor subunit essential for GM-CSF and IL-5 signaling, with melanoma cells engineered to produce GM-CSF. Tumor vaccination was effective in both GM-CSF-/- and IL-5-/- mice showing that protective immunization is independent of both endogenous cytokines. However, all c-/- animals developed tumor. Loss of tumor immunity in c-/- mice does not reflect global impairment in cell-mediated immunity, as contact hypersensitivity reaction to haptens is unaltered. The importance of tumor cell-derived GM-CSF was highlighted by recruitment of dendritic cells at the vaccination site in wild-type, GM-CSF-/- and IL-5-/- but not in c-/- mice. In the second model, vaccination with unmodified RENCA cells showed similar results with efficient immunization in BALB/c wild-type and GM-CSF-/- while all c-/- animals died. Altogether, our results strongly suggest that while endogenous GM-CSF and IL-5 are not required to induce tumor immunity, signaling through c receptor is critically needed for efficient cancer vaccination in both genetically modified GM-CSF-secreting tumor cells and a spontaneously immunogenic models.
