Intraperitoneal oxidative stress in rabbits with papillomavirus-associated head and neck cancer induces tumoricidal immune response that is adoptively transferable

Clin Cancer Res. 2014 Aug 15;20(16):4289-301. doi: 10.1158/1078-0432.CCR-14-0677. Epub 2014 Jun 18.


Purpose: How tumors evade or suppress immune surveillance is a key question in cancer research, and overcoming immune escape is a major goal for lengthening remission after cancer treatment. Here, we used the papillomavirus-associated rabbit auricular VX2 carcinoma, a model for studying human head and neck cancer, to reveal the mechanisms underlying the antitumorigenic effects of intraperitoneal oxidative stress following O3/O2-pneumoperitoneum (O3/O2-PP) treatment.

Experimental design: Solid auricular VX2 tumors were induced in immune-competent adult New Zealand White Rabbits. Animals were O3/O2-PP- or sham-treated, after which they underwent tumor ablation upon reaching no-go criteria. CD3(+) tumor-infiltrating lymphocytes (TIL) were evaluated by immunohistochemistry, and expression levels of 84 immune response genes were measured by quantitative real-time PCR. Adoptive transfer of peripheral blood leukocytes (PBL)-derived from animals with tumor regression-into control animals with progressing tumors was implemented to assess acquired tumor resistance functionally.

Results: Auricular VX2 tumors regressing after O3/O2-PP treatment exhibited increased levels of CD3(+) TILs; they also exhibited enhanced expression of genes that encode receptors involved in pattern recognition, molecules that are required for antigen presentation and T cell activation, and inflammatory mediators. Adoptive cell transfer of PBLs from donor rabbits with regressing tumors to recipient rabbits with newly implanted VX2 carcinoma resulted in acquired tumor resistance of the host and tumor regression.

Conclusion: Intraperitoneal oxidative stress effectively converts the immune response against the papillomavirus-associated rabbit VX2 carcinoma from tumor permissive to tumoricidal and leads to a sustainable, adoptively transferable oncolytic immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Carcinoma, Squamous Cell / immunology
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / prevention & control
  • Head and Neck Neoplasms / immunology
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / prevention & control*
  • Humans
  • Immunoenzyme Techniques
  • Immunotherapy, Adoptive
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / prevention & control*
  • Lung Neoplasms / secondary
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Oxidative Stress*
  • Oxygen / therapeutic use*
  • Ozone / therapeutic use*
  • Papillomaviridae / immunology*
  • Pneumoperitoneum / immunology
  • RNA, Messenger / genetics
  • Rabbits
  • Real-Time Polymerase Chain Reaction
  • Remission Induction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured


  • RNA, Messenger
  • Ozone
  • Oxygen