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

Keisuke Kosumi; Yohei Masugi; Juhong Yang; Zhi Rong Qian; Sun A Kim; Wanwan Li; Yan Shi; Annacarolina da Silva; Tsuyoshi Hamada; Li Liu; Mancang Gu; Tyler S Twombly; Yin Cao; David A Barbie; Katsuhiko Nosho; Hideo Baba; Wendy S Garrett; Jeffery A Meyerhardt; Edward L Giovannucci; Andrew T Chan; Charles S Fuchs; Shuji Ogino; Reiko Nishihara

doi:10.1080/2162402X.2017.1284720

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

Oncoimmunology. 2017 Jan 31;6(3):e1284720. doi: 10.1080/2162402X.2017.1284720. eCollection 2017.

Authors

Keisuke Kosumi¹, Yohei Masugi¹, Juhong Yang², Zhi Rong Qian¹, Sun A Kim³, Wanwan Li¹, Yan Shi¹, Annacarolina da Silva¹, Tsuyoshi Hamada¹, Li Liu⁴, Mancang Gu¹, Tyler S Twombly¹, Yin Cao⁵, David A Barbie¹, Katsuhiko Nosho⁶, Hideo Baba⁷, Wendy S Garrett⁸, Jeffery A Meyerhardt¹, Edward L Giovannucci⁹, Andrew T Chan¹⁰, Charles S Fuchs¹¹, Shuji Ogino¹², Reiko Nishihara¹³

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
² Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University , Tianjin, China.
³ Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine , Sapporo, Japan.
⁷ Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University , Kumamoto, Japan.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Abstract

Publication types

Grants and funding