Tumor-induced suppression of CTL expansion and subjugation by gp96-Ig vaccination.
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, RORgammat, IFNgamma, 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-beta 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.
Schreiber
Taylor H
TH
Sheila and David Fuente Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.
Deyev
Vadim V
VV
Rosenblatt
Joseph D
JD
Podack
Eckhard R
ER
D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000097:blood; D003602:Cytotoxicity, Immunologic; D051858:Forkhead Transcription Factors / Q000032:analysis; D020381:Interleukin-17 / Q000502:physiology; D008223:Lymphoma / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D018417:Th1 Cells / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000097:blood; D014611:Vaccination
D039481:CD11b Antigen; D019496:Cancer Vaccines; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; C053387:endoplasmin