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Tumor-Infiltrating Dendritic Cell Subsets of Progressive or Regressive Tumors Induce Suppressive or Protective Immune Responses

Research Unit, Division of Health Research, Saskatchewan Cancer Agency, Departments of Oncology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Requests for reprints: Jim Xiang, Research Unit, Division of Health Research, Saskatchewan Cancer Agency, Departments of Oncology and Immunology, College of Medicine, University of Saskatchewan, 20 Campus Drive, Saskatoon, Saskatchewan, Canada S7N 4H4. Phone: 306-655-2917; Fax: 306-655-2910; E-mail: JXiang{at}scf.sk.ca.

Tumor-infiltrating dendritic cells (TID) have an ambivalent role in regulation of tumor regression or growth. However, their precise natures and molecular mechanisms have not been elucidated. In this study, we studied TIDs recruited in progressive P815 and regressive P198 tumors of the same origin. Our data showed that P815 tumors contained CD4⁺8⁺ and CD4^–8^– TID₈₁₅ subsets, whereas P198 tumors contained CD4⁺8⁺ and CD4⁺8^– TID₁₉₈ subsets. They similarly stimulate allogeneic T cell proliferation and have nitric oxide–mediated cytotoxicity to tumor cells with an exception of CD4^–8^– TID₈₁₅ with less efficiency. The newly identified fourth CD4⁺8⁺ TID₈₁₅ or TID₁₉₈ subset and the CD4⁺8^– TID₁₉₈ all express high levels of IFN- and interleukin (IL)-6, whereas CD4^–8^– TID₈₁₅ secrete a marked level of transforming growth factor-ß. Vaccination of mice with P815 tumor lysate–pulsed CD4⁺8⁺ TID₈₁₅ or TID₁₉₈ and CD4⁺8^– TID₁₉₈ induced IFN-–secreting Th1 and effective CTL responses leading to protective immunity against P815 tumor, whereas CD4^–8^– TID₈₁₅ stimulated IL-10–expressing Tr1 responses leading to immune suppression. Transfer of CD4⁺ Tr1 cells obtained from CD4^–8^– TID₈₁₅-immunized wild-type, but not IL-10^–/– mice, into CD4⁺8⁺ TID₈₁₅ immunized mice abolished otherwise inevitable development of antitumor immunity. Taken together, our findings provide an important insight into immunologic alterations in progressive and regressive tumors and an implication for dendritic cell–based approaches in the design of cancer vaccines.

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