Abstract
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-naive 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 aninverse correlation between tumor-specific CTL expansion in the peripheral blood and tumor size. To identify immune cells and molecules associated with effective anti-tumor 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, ROHyt, IFNY, CCL8> CXCL9, and CXCLlO 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 CDllb+Gr-1+ cells and FoxP3+ cells. Furthermore, serum ELISAs revealed a significant elevation of transforming growth factor-ß 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 immuno-surveillance by preventing clonal expansion of tumor-specific CTL without inducing anergy.
| Original language | English |
|---|---|
| Pages (from-to) | 2026-2033 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 69 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 1 2009 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Tumor-induced suppression of CTL expansion and subjugation by gp96-lg vaccination. / Schreiber, Taylor H.; Deyev, Vadim V.; Rosenblatt, Joseph D; Podack, Eckhard R.
In: Cancer Research, Vol. 69, No. 5, 01.03.2009, p. 2026-2033.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tumor-induced suppression of CTL expansion and subjugation by gp96-lg vaccination
AU - Schreiber, Taylor H.
AU - Deyev, Vadim V.
AU - Rosenblatt, Joseph D
AU - Podack, Eckhard R.
PY - 2009/3/1
Y1 - 2009/3/1
N2 - 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-naive 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 aninverse correlation between tumor-specific CTL expansion in the peripheral blood and tumor size. To identify immune cells and molecules associated with effective anti-tumor 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, ROHyt, IFNY, CCL8> CXCL9, and CXCLlO 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 CDllb+Gr-1+ cells and FoxP3+ cells. Furthermore, serum ELISAs revealed a significant elevation of transforming growth factor-ß 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 immuno-surveillance by preventing clonal expansion of tumor-specific CTL without inducing anergy.
AB - 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-naive 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 aninverse correlation between tumor-specific CTL expansion in the peripheral blood and tumor size. To identify immune cells and molecules associated with effective anti-tumor 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, ROHyt, IFNY, CCL8> CXCL9, and CXCLlO 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 CDllb+Gr-1+ cells and FoxP3+ cells. Furthermore, serum ELISAs revealed a significant elevation of transforming growth factor-ß 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 immuno-surveillance by preventing clonal expansion of tumor-specific CTL without inducing anergy.
UR - http://www.scopus.com/inward/record.url?scp=62449170994&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62449170994&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-3706
DO - 10.1158/0008-5472.CAN-08-3706
M3 - Article
C2 - 19223534
AN - SCOPUS:62449170994
VL - 69
SP - 2026
EP - 2033
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 5
ER -