Tumor induced suppression of CTL expansion and subjugation by gp96-Ig vaccination
| Autor: | Taylor H. Schreiber, Joseph D. Rosenblatt, Vadim Deyev, Eckhard R. Podack |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Cytotoxicity
Immunologic Cancer Research Lymphoma medicine.medical_treatment Recombinant Fusion Proteins Biology Cancer Vaccines Article Mice Immune system Transforming Growth Factor beta Cell Line Tumor medicine Cytotoxic T cell Animals CD11b Antigen Membrane Glycoproteins Interleukin-17 Vaccination FOXP3 Forkhead Transcription Factors Immunotherapy Th1 Cells Immunosurveillance Chemokine CXCL10 Mice Inbred C57BL CTL Oncology Immunology biology.protein Antibody CD8 T-Lymphocytes Cytotoxic |
| Popis: | Established tumors suppress antitumor immune responses and induce tolerance by incompletely characterized mechanisms, and this phenomenon is an important barrier to tumor immunotherapy. Single vaccination with tumor cells expressing gp96-Ig stimulates robust expansion of tumor-specific CTLs in tumor-naïve mice and this expansion is inhibited by established tumors. Interestingly, frequent vaccinations restore antitumor immune responses in the presence of established tumors. Syngeneic EG7 tumor-bearing mice have heterogeneous responses to frequent vaccination with EG7-gp96-Ig, with 32% complete responders and 68% partial responders. Comparison of responders to nonresponders revealed an inverse correlation between tumor-specific CTL expansion in the peripheral blood and tumor size. To identify immune cells and molecules associated with effective antitumor immune responses, reverse transcription-PCR arrays were performed using cells isolated from the vaccination site. ELISAs, cellular phenotyping, and tumor immunohistochemistry were also performed comparing vaccine responders to nonresponders. These data show that up-regulation of T-bet, RORγt, IFNγ, CCL8, CXCL9, and CXCL10 at the vaccination site are associated with vaccine-induced antitumor immunity. These data correlate with increased CTL expansion in the peripheral blood of responders, increased infiltration of responder tumors by CD8+ cells and interleukin-17+ cells, and decreased infiltration of responder tumors by CD11b+Gr-1+ cells and FoxP3+ cells. Furthermore, serum ELISAs revealed a significant elevation of transforming growth factor-β in nonresponders as compared with responders. Interestingly, CD8+ T cells isolated from responders and nonresponders have equivalent cytotoxic activity in vitro. Taken together, our data suggest that established tumors may escape immunosurveillance by preventing clonal expansion of tumor-specific CTL without inducing anergy. [Cancer Res 2009;69(5):2026–33] |
| Databáze: | OpenAIRE |
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