Tumor sensitivity to IFN-gamma is required for successful antigen-specific immunotherapy of a transplantable mouse tumor model for HPV-transformed tumors

Cancer Immunol Immunother. 2005 May;54(5):477-88. doi: 10.1007/s00262-004-0610-0. Epub 2004 Oct 6.

Abstract

Purpose: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • Bacterial Vaccines / therapeutic use
  • Cancer Vaccines / immunology
  • Cancer Vaccines / therapeutic use*
  • Cell Line, Tumor
  • Cell Transformation, Viral
  • Disease Models, Animal
  • Female
  • Interferon-gamma / physiology*
  • Listeria monocytogenes / genetics
  • Listeria monocytogenes / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / immunology
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / immunology
  • Papillomaviridae / genetics
  • Papillomavirus E7 Proteins
  • Papillomavirus Infections / drug therapy*
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / immunology
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • Transcriptional Activation
  • Tumor Escape / immunology
  • Uterine Cervical Neoplasms / virology

Substances

  • Antigens, Neoplasm
  • Bacterial Vaccines
  • Cancer Vaccines
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Receptors, Interferon
  • oncogene protein E7, Human papillomavirus type 16
  • Interferon-gamma