Abstract
Purpose: Many human tumors lose responsiveness to IFN-γ, providing a possible mechanism for the tumor to avoid immune recognition and destruction. Here we investigate the importance of tumor responsiveness to IFN-γ in the successful immunotherapy of TC1 tumors that were immortalized with human papillomavirus proteins E6 and E7. Methods: To investigate the role of IFN-γ in vivo, we constructed a variant of TC1, TC1.mugR, that is unresponsive to IFN-γ due to overexpression of a dominant negative IFN-γ receptor. Results: Using recombinant Listeria monocytogenes that express HPV-16 E7 (Lm-LLO-E7) to stimulate an antitumor response, we demonstrate that sensitivity to IFN-γ is required for therapeutic efficacy in that Lm-LLO-E7 induces regression of TC1 tumors but not TC1.mugR. In addition, we show that tumor sensitivity to IFN-γ is not required for inhibition of tumor angiogenesis by Lm-LLO-E7 or for trafficking of CD4+ and CD8+ T cells to the tumor. However, it is required for penetration of lymphocytes into the tumor mass in vivo. Conclusions: Our findings identify a role for IFN-γ in immunity to TC1 tumors and show that loss of tumor responsiveness to IFN-γ poses a challenge to antigen-based immunotherapy.
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Abbreviations
- BHI:
-
Brain heart infusion
- CMV:
-
Cytomegalovirus
- CTL:
-
Cytotoxic T lymphocyte
- Hb:
-
Hemoglobin
- HPV:
-
Human papillomavirus
- IFN-γ:
-
Interferon-gamma
- IL-12:
-
Interleukin-12
- LLO:
-
Listeriolysin O
- Lm:
-
Listeria monocytogenes
- MHC:
-
Major histocompatibility class
- MME:
-
Metalloelastase
- NK:
-
Natural killer
- PBS:
-
Phosphate-buffered saline
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Acknowledgements
This work was supported by NIH grant CA69632 and ACS grant TURSG LIB-101399 (Y.P.), and NIH training grant T32CA09140 (G.L.B). We would like to thank Dr S. Farzana Hussain for critically reading this manuscript.
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Mary E. Dominiecki and Gregory L. Beatty contributed equally to this work.
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Dominiecki, M.E., Beatty, G.L., Pan, ZK. et al. Tumor sensitivity to IFN-γ is required for successful antigen-specific immunotherapy of a transplantable mouse tumor model for HPV-transformed tumors. Cancer Immunol Immunother 54, 477–488 (2005). https://doi.org/10.1007/s00262-004-0610-0
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DOI: https://doi.org/10.1007/s00262-004-0610-0