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Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors

Pirouz Daftarian1, Guang-Yun Song, Saima Ali

  • 1Laboratory of Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.

Cancer Research
|August 4, 2004
PubMed

Insights

This study shows that combining modified vaccinia Ankara-expressing p53 (MVAp53) with CpG oligodeoxynucleotides (CpG ODN) or CTLA-4 blockade enhances anti-tumor immunity. This approach effectively rejects established tumors and shows potential for cancer immunotherapy.

Area of Science:

  • Immunology
  • Oncology
  • Vaccinology

Background:

  • The p53 tumor suppressor is overexpressed in nearly 50% of human cancers, presenting a significant target for cancer immunotherapy.
  • Previous research established that immunization with modified vaccinia Ankara-expressing murine p53 (MVAp53) can reject established p53-overexpressing tumors without inducing autoimmunity.
  • Antibody-mediated cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade was previously shown to enhance MVAp53-mediated tumor rejection.

Purpose of the Study:

  • To investigate the role of synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine-phosphate-guanine (CpG) motifs (CpG ODN) in augmenting MVAp53-induced tumor rejection.
  • To compare the efficacy of CpG ODN and CTLA-4 blockade as adjuvants for MVAp53 immunotherapy.
  • To elucidate the immunological mechanisms underlying the adjuvant effects of CpG ODN and CTLA-4 blockade in MVAp53 immunotherapy.

Main Methods:

  • Tumor rejection was assessed in mice bearing various established tumors (murine mammary carcinomas, sarcomas, colon carcinomas) following immunization with MVAp53, alone or in combination with CpG ODN or CTLA-4 blockade.
  • Monoclonal antibody depletion experiments were performed to determine the roles of CD8+ T cells, CD4+ T cells, and natural killer (NK) cells.
  • Experiments in Toll-like Receptor 9 (TLR9)-deficient and interleukin-6 (IL-6)-deficient mice were conducted to assess the involvement of these pathways.

Main Results:

  • Co-administration of MVAp53 with CpG ODN led to tumor rejection in multiple mouse models, an effect comparable to MVAp53 plus CTLA-4 blockade.
  • Both CpG ODN and CTLA-4 blockade adjuvant effects were dependent on CD8+ T cells; CpG ODN also showed partial NK cell dependence, while CTLA-4 blockade was partially CD4+ T cell dependent.
  • CpG ODN was ineffective in TLR9(-/-) and IL-6(-/-) mice, whereas CTLA-4 blockade remained functional in these knockout models.
  • Both adjuvants enhanced p53-specific cytotoxicity when combined with MVAp53, exhibiting an additive effect.
  • The combination of CpG ODN and CTLA-4 blockade demonstrated synergistic tumor rejection against palpable tumors.

Conclusions:

  • CpG ODN and CTLA-4 blockade can significantly augment MVAp53-mediated antitumor immunity.
  • The combination of CpG ODN and CTLA-4 blockade exhibits synergistic activity, leading to potent rejection of established tumors.
  • This cell-free immunotherapy strategy holds promise for clinical evaluation in cancer patients.

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