Cooperative induction of a tolerogenic dendritic cell phenotype by cytokines secreted by pancreatic carcinoma cells

被引:97
作者
Bellone, Graziella
Carbone, Anna
Smirne, Carlo
Scirelli, Tiziana
Buffolino, Alessandra
Novarino, Anna
Stacchini, Alessandra
Bertetto, Oscar
Palestro, Giorgio
Sorio, Claudio
Scarpa, Aldo
Emanuelli, Giorgio
Rodeck, Ulrich
机构
[1] Univ Turin, Dept Clin Physiopathol, I-10126 Turin, Italy
[2] Univ Turin, Dept Biomed Sci & Human Oncol, I-10126 Turin, Italy
[3] San Giovanni Battista Hosp, Dept Pathol Anat, Turin, Italy
[4] San Giovanni Battista Hosp, Dept Oncol, Turin, Italy
[5] San Giovanni Battista Hosp, Dept Gastroenterol & Clin Nutr, Turin, Italy
[6] Univ Verona, Dept Pathol, I-37100 Verona, Italy
[7] Thomas Jefferson Univ, Dept Dermatol, Philadelphia, PA 19107 USA
关键词
D O I
10.4049/jimmunol.177.5.3448
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Ag presentation by dendritic cells (DC) is essential to effective antitumor T cell responses in cancer patients. Depending on their origin, maturation state, and the ambient cytokine milieu, DC can differentiate into distinct subpopulations, which preferentially either induce Th1 cell activation (CD11c(+),CD123(-) myeloid DC (MDC)) or immunosuppressive T cell development (CD11c(-),CD123(+) plasmacytoid DC (PDC)). The present study was undertaken to characterize the effects of pancreatic carcinoma cell-derived cytokines on immature monocyte-derived DC (iMo-DC) in vitro and in vivo. Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma. Moreover, in tumor-patient peripheral blood, the ratio of MDC to PDC cells was lower than in healthy controls due to reduced numbers of MDC CD11c(+) cells. Importantly, rather than a single cytokine, a combination of tumor-derived cytokines was responsible for these effects; these were primarily TGF-beta, IL-10, and IL-6, but not vascular endothelial growth factor. In summary, we have identified an array of pancreatic carcinoma-derived cytokines that cooperatively affect iMo-DC activation in a manner consistent with ineffective antitumor immune responses.
引用
收藏
页码:3448 / 3460
页数:13
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