Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

A. Covre, S. Coral, H. Nicolay, G. Parisi, C. Fazio, F. Colizzi, E. Fratta, A. M. Di Giacomo, L. Sigalotti, P. G. Natali, M. Maio

Research output: Contribution to journalArticle

Abstract

The multifaceted immunomodulatory activity of DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells; thus, we predicted they could be utilized to design new immunotherapeutic combinations in cancer. Testing this hypothesis, the antitumor efficacy of the DNA hypomethylating agent 5-aza-2′-deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated. Murine mammary carcinoma TS/A or mesothelioma AB1 cells were injected in BALB/c, athymic nude, and SCID/Beige mice that were treated with 5-AZA-CdR, mAb 9H10, or their combination. Tumor volumes were captured at different time-points; molecular and immunohistochemical assays investigated changes in neoplastic and normal tissues. A significant antitumor effect of 5-AZA-CdR combined with mAb 9H10 was found: compared to controls, a 77% (p <0.01), 54% (p <0.01) and 33% (p = 0.2) decrease in TS/A tumor growth was induced by 5-AZA-CdR combined with mAb 9H10, 5-AZA-CdR or mAb 9H10, respectively. These antitumor activities were confirmed utilizing the AB1 model. 5-AZA-CdR-based regimens induced a promoter-demethylation-sustained tumor expression of cancer testis antigens. MHC class I expression was up-regulated by 5-AZA-CdR. Antitumor efficacy of 5-AZA-CdR in athymic nude and SCID/Beige mice was not increased by mAb 9H10. In BALB/c mice, combined treatment induced the highest tumor infiltration by CD3+ lymphocytes, which included both CD8+ and CD4+ T cells; no such infiltrates were observed in normal tissues. This significant immune-related antitumor activity of 5-AZA-CdR combined with CTLA-4 blockade, demonstrated in highly aggressive mouse tumor models, provides a strong scientific rationale to implement epigenetically-based immunotherapies in cancer patients.

Original languageEnglish
JournalOncoImmunology
Volume4
Issue number8
DOIs
Publication statusPublished - Aug 3 2015

Keywords

  • cancer
  • CTLA-4
  • DNA methylation
  • immune responses
  • immunomodulation
  • immunotherapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

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    Covre, A., Coral, S., Nicolay, H., Parisi, G., Fazio, C., Colizzi, F., Fratta, E., Di Giacomo, A. M., Sigalotti, L., Natali, P. G., & Maio, M. (2015). Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models. OncoImmunology, 4(8). https://doi.org/10.1080/2162402X.2015.1019978