title: 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, andKRAS, BRAF, andPIK3CAmutations. Tumor SQSTM1 expression level was inversely associated with FOXP3+cell density (ptrend= 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kosumi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Masugi
authors.affiliation: 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.
authors.forename: Juhong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.
authors.forename: Sun A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Wanwan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Annacarolina
authors.initials: A
authors.lastname: da Silva
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hamada
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Mancang
authors.initials: M
authors.lastname: Gu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Tyler S
authors.initials: TS
authors.lastname: Twombly
authors.affiliation: 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.
authors.forename: Yin
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.affiliation: Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine , Sapporo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University , Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.affiliation: 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.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Garrett
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA.
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Meyerhardt
authors.affiliation: 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.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.affiliation: 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.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: 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.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: 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.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
keywords: Adenocarcinoma; colorectum; immunoprevention; immunotherapy; molecular pathology