MicroRNA MIR21 and T cells in colorectal cancer

Kosuke Mima, Reiko Nishihara, Jonathan A. Nowak, Sun A. Kim, Mingyang Song, Kentaro Inamura, Yasutaka Sukawa, Atsuhiro Masuda, Juhong Yang, Ruoxu Dou, Katsuhiko Nosho, Hideo Baba, Edward L. Giovannucci, Michaela Bowden, Massimo Loda, Marios Giannakis, Adam J. Bass, Glenn Dranoff, Gordon J. Freeman, Andrew T. ChanCharles S. Fuchs, Zhi Rong Qian, Shuji Ogino

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Abstract

The complex interactions between colorectal neoplasia and immune cells in the tumor microenvironment remain to be elucidated. Experimental evidence suggests that microRNA MIR21 (miR-21) suppresses antitumor T-cell-mediated immunity. Thus, we hypothesized that tumor MIR21 expression might be inversely associated with T-cell density in colorectal carcinoma tissue. Using 538 rectal and colon cancer cases from the Nurses' Health Study and the Health Professionals Follow-up Study, we measured tumor MIR21 expression by a quantitative reverse-transcription PCR assay. Densities of CD3+, CD8+, CD45RO (PTPRC)+, and FOXP3+ cells in tumor tissue were determined by tissue microarray immunohistochemistry and computer-assisted image analysis. Ordinal logistic regression analysis was conducted to assess the association of MIR21 expression (ordinal quartiles as a predictor variable) with T-cell density (ordinal quartiles as an outcome variable), adjusting for tumor molecular features, including microsatellite instability; CpG island methylator phenotype; KRAS, BRAF, and PIK3CA mutations; and LINE-1 methylation. We adjusted the two-sided a level to 0.012 for multiple hypothesis testing. Tumor MIR21 expression was inversely associated with densities of CD3+ and CD45RO+ cells (Ptrend <0.0005). Themultivariateodds ratio of the highest versus lowest quartile of MIR21 for a unit increase in quartile categories of CD3+ or CD45RO+ cells was 0.44 [95% confidence interval (CI), 0.28 to 0.68] or 0.41 (95% CI, 0.26-0.64), respectively. Our data support a possible role of tumor epigenetic deregulation by noncoding RNA in suppressing the antitumor T-cell-mediated adaptive immune response and suggest MIR21 as a potential target for immunotherapy and prevention in colorectal cancer.

Original languageEnglish
Pages (from-to)33-40
Number of pages8
JournalCancer immunology research
Volume4
Issue number1
DOIs
Publication statusPublished - 2016 Jan 1
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Immunology

Cite this

Mima, K., Nishihara, R., Nowak, J. A., Kim, S. A., Song, M., Inamura, K., Sukawa, Y., Masuda, A., Yang, J., Dou, R., Nosho, K., Baba, H., Giovannucci, E. L., Bowden, M., Loda, M., Giannakis, M., Bass, A. J., Dranoff, G., Freeman, G. J., ... Ogino, S. (2016). MicroRNA MIR21 and T cells in colorectal cancer. Cancer immunology research, 4(1), 33-40. https://doi.org/10.1158/2326-6066.CIR-15-0084