title: Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis.
abstract: The composition of tumor-targeted T cell infiltrates is a major prognostic factor in colorectal cancer (CRC) outcome; however, the functional role of these populations in prolonging patient survival remains unclear. Here, we evaluated 190 patients with CRC for the presence of functionally active tumor-infiltrating lymphocytes (TILs), the tumor specificity of these TILs, and the correlation between patient TILs and long-term survival. Using intracytoplasmic cytokine staining in conjunction with HLA multimers loaded with tumor peptide and antigen-specific cytokine secretion assays, we determined that TNF-α expression delineates a population of tumor antigen-specific (TA-specific) cytotoxic T lymphocytes (CTLs) present within tumors from patients with CRC. Upregulation of TNF-α expression in TILs strongly correlated with an increase in the total amount of intratumoral TNF-α, which is indicative of tumor-specific CTL activity. Moreover, a retrospective multivariate analysis of 102 patients with CRC, which had multiple immune parameters evaluated, revealed that increased TNF-α concentration was an independent prognostic factor. Together, these results indicate that the prognostic impact of T cell infiltrates for CRC maybe largely based on subpopulations of active TA-specific T cells within the tumor, suggesting causal implication for these cells in patient survival. Additionally, these results support the use of intratumoral TNF-α, which is indicative of T cell function, as a prognostic parameter for CRC.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reissfelder
authors.forename: Slava
authors.initials: S
authors.lastname: Stamova
authors.forename: Christina
authors.initials: C
authors.lastname: Gossmann
authors.forename: Marion
authors.initials: M
authors.lastname: Braun
authors.forename: Andreas
authors.initials: A
authors.lastname: Bonertz
authors.forename: Ute
authors.initials: U
authors.lastname: Walliczek
authors.forename: Mario
authors.initials: M
authors.lastname: Grimm
authors.forename: Nuh N
authors.initials: NN
authors.lastname: Rahbari
authors.forename: Moritz
authors.initials: M
authors.lastname: Koch
authors.forename: Maral
authors.initials: M
authors.lastname: Saadati
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000276:immunology; D011446:Prospective Studies; D012189:Retrospective Studies; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D009363:Neoplasm Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha