Two Distinct Pathways of Immuno-Modulation Improve Potency of p53 Immunization in Rejecting Established Tumors

Autor: Joshua D. I. Ellenhorn, Jeff Longmate, Don J. Diamond, Guang Yun Song, Saima Ali, Pirouz Daftarian, Moshe Faynsod
Rok vydání: 2004
Předmět:
Cancer Research
CpG Oligodeoxynucleotide
medicine.medical_treatment
Mammary Neoplasms
Animal
Receptors
Cell Surface
CD8-Positive T-Lymphocytes
Natural killer cell
Mice
Adjuvants
Immunologic
Cancer immunotherapy
Antigens
CD
Cricetinae
medicine
Animals
Humans
CTLA-4 Antigen
Interleukin 6
Cells
Cultured
Mice
Knockout
Mice
Inbred BALB C
biology
Interleukin-6
Homozygote
Antibodies
Monoclonal
Drug Synergism
hemic and immune systems
Immunotherapy
Cytotoxicity Tests
Immunologic
Antigens
Differentiation
Combined Modality Therapy
Toll-Like Receptor 9
Blockade
DNA-Binding Proteins
Killer Cells
Natural
Mice
Inbred C57BL
medicine.anatomical_structure
Oligodeoxyribonucleotides
Oncology
CpG site
Colonic Neoplasms
biology.protein
Cancer research
Female
Immunization
Sarcoma
Experimental
Tumor Suppressor Protein p53
Signal Transduction
Zdroj: Cancer Research. 64:5407-5414
ISSN: 1538-7445
0008-5472
Popis: 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.
Databáze: OpenAIRE
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