title: Genetic evidence that intratumoral T-cell proliferation and activation are associated with recurrence and survival in patients with resected colorectal liver metastases.
abstract: Though immune responses correlate with prognosis in primary colorectal cancer, the role of tumor immunity in metastatic disease is less clear. We hypothesized that patient survival and tumor recurrence correlate with transcriptional evidence of lymphocyte proliferation/activation in resected colorectal cancer liver metastases (CRLM). Microarray gene analysis was performed on liver tumor specimens from 96 patients who underwent resection for CRLM. A Cox proportional hazards model identified genes associated with overall survival (OS) and recurrence-free survival (RFS). Conventional gene ontology (GO) enrichment analysis ranked biologically relevant processes. Survival probabilities of prioritized processes were assessed. Protein expression was validated with immunohistochemistry in an independent set of patients. GO analysis identified and ranked unique biologic processes that correlated with survival. Genes that specifically functioned in the biologic process of "T-cell proliferation" were significant predictors of OS (P = 0.01), and both "T-cell proliferation" and "activation" were highly associated with RFS (P ≤ 0.01). Analysis of genes in these GO categories identified increased TNFSF14/LIGHT expression to be most associated with improved OS and RFS (P ≤ 0.0006). Immunohistochemistry of an independent validation set of CRLM confirmed that both increased tumor-infiltrating lymphocytes (TIL) and higher LIGHT expression on TILs were associated with improved OS and RFS. Differential expression of genes involved in T-cell proliferation/activation was associated with survival outcomes in a large number of surgical patients who underwent resection of CRLM. These biologic functions determined by GO analysis of the tumor microenvironment have identified specific immune-related genes that may be involved in an antitumor immune response.
authors.affiliation: Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, Illinois. amaker@uic.edu.
authors.forename: Ajay V
authors.initials: AV
authors.lastname: Maker
authors.affiliation: Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Elliot
authors.initials: E
authors.lastname: Weisenberg
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.affiliation: Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Simon
authors.initials: S
authors.lastname: Turcotte
authors.affiliation: Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shishir
authors.initials: S
authors.lastname: Maithel
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.affiliation: Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Leslie
authors.initials: L
authors.lastname: Blumgart
authors.affiliation: Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong
authors.affiliation: Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: William R
authors.initials: WR
authors.lastname: Jarnagin
authors.affiliation: Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: DeMatteo
authors.affiliation: Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael I
authors.initials: MI
authors.lastname: D'Angelica
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary* / Q000601:surgery; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D046888:Tissue Array Analysis / Q000379:methods; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14