Tumor sensitivity to IFN-gamma is required for successful antigen-specific immunotherapy of a transplantable mouse tumor model for HPV-transformed tumors.
OBJECTIVE
Many human tumors lose responsiveness to IFN-gamma, providing a possible mechanism for the tumor to avoid immune recognition and destruction. Here we investigate the importance of tumor responsiveness to IFN-gamma in the successful immunotherapy of TC1 tumors that were immortalized with human papillomavirus proteins E6 and E7.


METHODS
To investigate the role of IFN-gamma in vivo, we constructed a variant of TC1, TC1.mugR, that is unresponsive to IFN-gamma due to overexpression of a dominant negative IFN-gamma 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-gamma 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-gamma 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-gamma in immunity to TC1 tumors and show that loss of tumor responsiveness to IFN-gamma poses a challenge to antigen-based immunotherapy.
Dominiecki
Mary E
ME
Department of Microbiology, University of Pennsylvania, 323 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104-6076, USA.
Beatty
Gregory L
GL
Pan
Zhen-Kun
ZK
Neeson
Paul
P
Paterson
Yvonne
Y
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D001428:Bacterial Vaccines / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000502:physiology*; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D027383:Papillomaviridae / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015533:Transcriptional Activation; D019139:Tumor Escape / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000821:virology
D000951:Antigens, Neoplasm; D001428:Bacterial Vaccines; D019496:Cancer Vaccines; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D017471:Receptors, Interferon; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma