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

Pirouz Daftarian, Guang Yun Song, Saima Ali, Moshe Faynsod, Jeff Longmate, Don J. Diamond, Joshua D.I. Ellenhorn

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

The p53 gene product is overexpressed by almost 50% of cancers, making it an ideal target for cancer immunotherapy. We previously demonstrated rejection of established p53-overexpressing tumors without stimulating autoimmunity by immunization with modified vaccinia Ankara-expressing murine p53 (MVAp53). Tumor rejection was enhanced through antibody-mediated CTL-associated antigen 4 (CTLA-4) blockade. We examined the role of synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine-phosphate-guanine (CpG) motifs (CpG ODN) in enhancing MVAp53-mediated tumor rejection. CpG ODN with MVAp53 resulted in tumor rejection in BALB/c mice bearing poorly immunogenic 11A-1 murine mammary carcinomas or Meth A sarcomas and C57Bl/6 mice bearing MC-38 colon carcinomas. The effect was similar to that seen in tumor-bearing mice treated with MVAp53 along with CTLA-4 blockade. Monoclonal antibody depletion experiments demonstrated that the adjuvant effects of CpG ODN and CTLA-4 blockades were CD8 dependent. CpG ODN were partially natural killer cell dependent and ineffective in Toll-like Receptor 9-/- and interleukin 6-/- mice, whereas CTLA-4 blockade was partially CD4 dependent and functional in Toll-like Receptor 9-/- and interleukin 6-/- mice. In addition, when administered with MVAp53, both adjuvants enhanced p53-specific cytotoxicity and demonstrated an additive effect when combined. The combination of CpG ODN and CTLA-4 blockade worked synergistically to reject palpable 11A-1 and MC-38 tumors. These experiments demonstrate the potential for augmenting MVAp53-mediated antitumor immunity using CpG ODN and CTLA-4 blockade. This cell-free immunotherapy approach is a candidate for evaluation in cancer patients.

Original languageEnglish (US)
Pages (from-to)5407-5414
Number of pages8
JournalCancer Research
Volume64
Issue number15
DOIs
StatePublished - Aug 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors'. Together they form a unique fingerprint.

  • Cite this

    Daftarian, P., Song, G. Y., Ali, S., Faynsod, M., Longmate, J., Diamond, D. J., & Ellenhorn, J. D. I. (2004). Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors. Cancer Research, 64(15), 5407-5414. https://doi.org/10.1158/0008-5472.CAN-04-0169