Tumor-induced interleukin-10 inhibits type 1 immune responses directed at a tumor antigen as well as a non-tumor antigen present at the tumor site.
Interleukin (IL)-10 is a potent immunosuppressive cytokine that has been found to be present at the tumor site in a wide variety of human cancers, including transitional cell carcinoma of the bladder. Using a murine bladder tumor (MB49), which we show to express the male transplantation antigen (HY), we tested the hypothesis that IL-10 at the tumor site can block the generation of a tumor-specific type 1 immune response. We show that, despite its expression of HY, MB49 fails to prime for an HY-specific type 1 (IFN-gamma) response in normal female mice. Although MB49 does not constitutively produce IL-10, our data support a model whereby MB49 induces infiltrating cells to produce IL-10. This feature rendered the IL-10 knockout (KO) mouse, whose infiltrating cells are incapable of IL-10 production, a suitable model in which to study MB49 in the absence of IL-10. When injected into IL-10 KO mice, MB49 does prime for an HY-specific, type 1 immune response. Furthermore, IL-10 KO mice show prolonged survival and an increased capacity to reject tumors as compared with normal mice. We also tested the ability of tumor-induced IL-10 to inhibit immunization to a non-tumor antigen present at the tumor site. When vaccinia virus encoding beta-galactosidase (beta-gal) is injected into the tumors of normal mice, no beta-gal-specific IFN-gamma response is mounted. However, when this same viral construct is injected into the tumors of IL-10 KO mice, it produces a strong beta-gal-specific, IFN-gamma response. These studies demonstrate that tumor-induced IL-10 can block the generation of a tumor-specific type 1 immune response as well as subvert attempts to elicit a type 1 immune response to a non-tumor antigen at the tumor site.
Halak
B K
BK
Kimmel Cancer Center, Division of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Maguire
H C
HC
Lattime
E C
EC
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D002295:Carcinoma, Transitional Cell / Q000276:immunology; D005260:Female; D006182:H-Y Antigen / Q000032:analysis / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology
D000951:Antigens, Neoplasm; D006182:H-Y Antigen; D016753:Interleukin-10; D007371:Interferon-gamma