Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis

• Published in: The Journal of clinical investigation 2015-02, Vol.125 (2), p.739-751
• Main Authors: Reissfelder, Christoph, Stamova, Slava, Gossmann, Christina, Braun, Marion, Bonertz, Andreas, Walliczek, Ute, Grimm, Mario, Rahbari, Nuh N, Koch, Moritz, Saadati, Maral, Benner, Axel, Büchler, Markus W, Jäger, Dirk, Halama, Niels, Khazaie, Khashayarsha, Weitz, Jürgen, Beckhove, Philipp
• Format: Article
• Language: English
• Subjects: Analysis; Antigens; Biomarkers; Biomedical research; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cloning; Colorectal cancer; Colorectal Neoplasms - immunology; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Cytotoxicity; Disease-Free Survival; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic - immunology; Humans; Male; Medical prognosis; Neoplasm Proteins - immunology; Patients; Physiological aspects; Prognosis; Properties; Prospective Studies; Retrospective Studies; Software; Studies; Survival analysis; Survival Rate; T cells; Tumor Necrosis Factor-alpha - immunology; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI74894

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.