Tumor SQSTM1 (p62) expression and T cells in colorectal cancer

ABSTRACT

Evidence suggests that activation of autophagy in neoplastic cells potentiates antitumor immunity through cross-presentation of tumor-associated antigens to T cells and release of immune mediators. The SQSTM1 (sequestosome 1, p62) protein is degraded by activated autophagy, and might enhance immune response to tumor cells. We hypothesized that tumor SQSTM1 expression level might be inversely associated with T-cell densities in colorectal carcinoma tissue. We evaluated tumor SQSTM1 expression by immunohistochemistry in 601 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. Ordinal logistic regression analyses were conducted to assess the association of tumor SQSTM1 expression with CD3⁺, CD8⁺, CD45RO (PTPRC)⁺, or FOXP3⁺ cell density in tumor tissue, controlling for potential confounders, including tumor status of microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. Tumor SQSTM1 expression level was inversely associated with FOXP3⁺ cell density (p_trend = 0.006), but not with CD3⁺, CD8⁺, or CD45RO⁺ cell density (with the adjusted α level of 0.01 for multiple hypothesis testing). For a unit increase in quartile categories of FOXP3⁺ cell density, multivariable odds ratios were 0.66 [95% confidence interval (CI), 0.45–0.98] for intermediate-level SQSTM1 expression, and 0.55 (95% CI, 0.36–0.83) for high-level SQSTM1 expression, compared with low-level SQSTM1 expression. Tumor SQSTM1 expression is inversely associated with FOXP3⁺ cell density in colorectal cancer tissue, suggesting a possible role of SQSTM1-expressing carcinoma cells on regulatory T cells in the tumor microenvironment.

KEYWORDS:

• Adenocarcinoma
• colorectum
• immunoprevention
• immunotherapy
• molecular pathology

Disclosure of potential conflict of interest

A.T.C. previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pozen, Inc., and Pfizer, Inc. This study was not funded by Bayer Healthcare, Millennium Pharmaceuticals, Pozen, Inc., or Pfizer, Inc. The other authors declare that they have no conflicts of interest.

Acknowledgments

We would like to thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

Funding

This work was supported by U.S. National Institutes of Health (NIH) grants [P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to C.S.F.; R01 CA137178 to A.T.C.; R01 CA151993 to S.O.; R35 CA197735 to S.O.; and K07 CA190673 to R.N.]; Nodal Award (to S.O.) from the Dana-Farber Harvard Cancer Center; and by grants from the Project P Fund, the Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. J.Y is supported by National Natural Science Foundation of China (81200612); Tianjin City High School Science & Technology Fund Planning Project (20102217). K.K. is supported by a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japanese Society for the Promotion of Science. Y.M. is supported by a fellowship grant of the Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research. T.H. was supported by a fellowship grant from the Uehara Memorial Foundation and by a grant from the Mochida Memorial Foundation for Medical and Pharmaceutical Research.