TY - JOUR
T1 - Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis
AU - Reissfelder, Christoph
AU - Stamova, Slava
AU - Gossmann, Christina
AU - Braun, Marion
AU - Bonertz, Andreas
AU - Walliczek, Ute
AU - Grimm, Mario
AU - Rahbari, Nuh N.
AU - Koch, Moritz
AU - Saadati, Maral
AU - Benner, Axel
AU - Büchler, Markus W.
AU - Jäger, Dirk
AU - Halama, Niels
AU - Khazaie, Khashayarsha
AU - Weitz, Jürgen
AU - Beckhove, Philipp
PY - 2015/2/2
Y1 - 2015/2/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84922132326&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922132326&partnerID=8YFLogxK
U2 - 10.1172/JCI74894
DO - 10.1172/JCI74894
M3 - Article
C2 - 25562322
AN - SCOPUS:84922132326
SN - 0021-9738
VL - 125
SP - 739
EP - 751
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -