Tumor-Induced Suppression of CTL Expansion and Subjugation by gp96-Ig Vaccination

Sheila and David Fuente Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.
Cancer Research (Impact Factor: 9.33). 03/2009; 69(5):2026-33. DOI: 10.1158/0008-5472.CAN-08-3706
Source: PubMed


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.

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    • "A major impediment to cancer therapy is tumor-induced immunosuppression and tumor evasion of antitumor immune responses, which ultimately render the host tolerant to tumor-associated antigens (Goldman and DeFrancesco 2009; Kirkwood et al. 2008; Wei et al. 2008; Schreiber et al. 2009). "
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    Preview · Article · Dec 2011
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    • "Data are representative of two independent experiments. expansion [36]. Our previous study showed that high dose (100 ␮g) of gp96 immunization could result in detrimental bystander effects on HBV-specific T cells stimulation by activation of Treg in HBVnaïve mice, indicating a balance between Treg and CTLs mediated by gp96. "
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