التفاصيل البيبلوغرافية
| العنوان: |
Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models. |
| المؤلفون: |
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 |
| المصدر: |
OncoImmunology; Aug2015, Vol. 4 Issue 8, p00-00, 0p |
| مصطلحات موضوعية: |
DNA restriction enzymes, IMMUNOSUPPRESSIVE agents, ANIMAL models of cancer, MONOCLONAL antibodies, TUMOR growth, MAJOR histocompatibility complex, IMMUNOHISTOCHEMISTRY, LABORATORY mice |
| مستخلص: |
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. [ABSTRACT FROM PUBLISHER] |
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| قاعدة البيانات: |
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