دورية أكاديمية
COX-2 Inhibitors Decrease Expression of PD-L1 in Colon Tumors and Increase the Influx of Type I Tumor-infiltrating Lymphocytes.
| العنوان: | COX-2 Inhibitors Decrease Expression of PD-L1 in Colon Tumors and Increase the Influx of Type I Tumor-infiltrating Lymphocytes. |
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| المؤلفون: | Cecil DL; UW Medicine Cancer Vaccine Institute, University of Washington, Seattle, Washington., Gad EA; UW Medicine Cancer Vaccine Institute, University of Washington, Seattle, Washington., Corulli LR; UW Medicine Cancer Vaccine Institute, University of Washington, Seattle, Washington., Drovetto N; UW Medicine Cancer Vaccine Institute, University of Washington, Seattle, Washington., Lubet RA; NCI, Bethesda, Maryland., Disis ML; UW Medicine Cancer Vaccine Institute, University of Washington, Seattle, Washington. |
| المصدر: | Cancer prevention research (Philadelphia, Pa.) [Cancer Prev Res (Phila)] 2022 Apr 01; Vol. 15 (4), pp. 225-231. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101479409 Publication Model: Print Cited Medium: Internet ISSN: 1940-6215 (Electronic) Linking ISSN: 19406215 NLM ISO Abbreviation: Cancer Prev Res (Phila) Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research |
| مواضيع طبية MeSH: | Colonic Neoplasms*/drug therapy , Colonic Neoplasms*/metabolism , Colonic Neoplasms*/prevention & control , Lymphocytes, Tumor-Infiltrating*, Animals ; B7-H1 Antigen/metabolism ; CD8-Positive T-Lymphocytes ; Cyclooxygenase 2 Inhibitors/pharmacology ; Mice |
| مستخلص: | Colon cancer is initiated under inflammatory conditions associated with upregulation of immune checkpoint proteins. We evaluated immune modulation induced by nonsteroidal anti-inflammatory agents used for colon cancer prevention. Both celecoxib and naproxen inhibited polyp growth in APC Min mice. Treatment of mice with either drug significantly decreased PD-L1 expression on polyps in a dose-dependent manner (P < 0.0001 for both). The decrease in PD-L1 was associated with an influx of CD8+ T cells into polyps (P < 0.0001, celecoxib; P = 0.048, naproxen) compared with lesions from untreated animals and correlated with disease control. Naproxen is a nonselective inhibitor of both COX-1 and COX-2, and we questioned the role of the different cyclooxygenases in PD-L1 regulation. Silencing either COX-2 or COX-1 RNA in the murine colon cancer cell line MC38, reduced PD-L1 expression by 86% in COX-2-silenced cells (P < 0.0001) while there was little effect with COX-1 siRNA compared with control. Naproxen could inhibit the growth of MC38 in vivo. Naproxen-treated mice demonstrated a significant reduction in MC38 growth as compared with control (P < 0001). Both Tbet+ CD4 and CD8 tumor-infiltrating lymphocytes (TIL) were significantly increased (P = 0.04 and P = 0.038, respectively) without a concurrent increase in GATA3+ TIL (P > 0.05). CD8+ TIL highly expressed the activation marker, CD69. Not only was PD-L1 expression decreased on tumors, but LAG3+CD8+ T cells and PD-1 and LAG3 expression on regulatory T cells was also reduced (P = 0.008 and P = 0.002, respectively). These data demonstrate COX-2 inhibitors significantly decrease PD-L1 in colonic lesions and favorably impact the phenotype of tumor-infiltrating lymphocytes to control tumor growth. Prevention Relevance: Nonsteroidal anti-inflammatories (NSAID) are an essential component of any combination chemoprevention of colon cancer. We show NSAID treatment reduces PD-L1 expression on intestinal tumor cells. NSAID regulation of PD-L1 is dependent on COX-2 expression. These data underscore an important immunologic mechanism of action for NSAID in colon cancer prevention. See related Spotlight, p. 209. (©2022 American Association for Cancer Research.) |
| التعليقات: | Comment in: Cancer Prev Res (Phila). 2022 Apr 1;15(4):209-211. (PMID: 35373258) |
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| معلومات مُعتمدة: | HHSN261201200013I United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (B7-H1 Antigen) 0 (Cyclooxygenase 2 Inhibitors) |
| تواريخ الأحداث: | Date Created: 20220106 Date Completed: 20220405 Latest Revision: 20221003 |
| رمز التحديث: | 20240829 |
| مُعرف محوري في PubMed: | PMC8983455 |
| DOI: | 10.1158/1940-6207.CAPR-21-0227 |
| PMID: | 34987061 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1940-6215 |
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| DOI: | 10.1158/1940-6207.CAPR-21-0227 |