Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis
Christoph Reissfelder, … , Jürgen Weitz, Philipp Beckhove
Christoph Reissfelder, … , Jürgen Weitz, Philipp Beckhove
Published December 22, 2014
Citation Information: J Clin Invest. 2015;125(2):739-751. https://doi.org/10.1172/JCI74894.
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Research Article

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

Christoph Reissfelder, Slava Stamova, Christina Gossmann, Marion Braun, Andreas Bonertz, Ute Walliczek, Mario Grimm, Nuh N. Rahbari, Moritz Koch, Maral Saadati, Axel Benner, Markus W. Büchler, Dirk Jäger, Niels Halama, Khashayarsha Khazaie, Jürgen Weitz, Philipp Beckhove

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Figure 1

Increased TNF-α expression in activated TCs.

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Increased TNF-α expression in activated TCs. (A) TNF-α expression in pol...
(A) TNF-α expression in polyclonally activated (middle column) but not in unstimulated (right column) CD4+ and CD8+ TILs from one representative patient with CRC (n = 4) was detected by flow cytometry using TNF-α–specific mAb or a respective isotype mAb as negative control (left column). Numbers in dot plots indicate proportions (%) of TNF-α–positive cells among gated cells. (B and C) Mean proportions of TNF-α–expressing CD8+ or CD4+ TCs in rested TILs from 4 patients with CRC (B) and in the blood of 5 patients with CRC (C), without (white bars) or after polyclonal stimulation (gray bars), are shown as the percentage of the respective TC subset. Before analysis, freshly isolated TILs were rested overnight without stimulation. Error bars show mean + SD. (D and E) Proportions of TNF-α–positive CD8+ (D) or CD4+ (E) TCs in freshly isolated TCs from CRC tissue (gray circles) or corresponding normal colonic mucosa (white circles) of 8 patients with CRC. Circles indicate values from individual samples. Mean values are indicated by black lines. (F) Concentrations of TNF-α protein in CRC tissue and corresponding normal colonic mucosa from 14 patients (mean + SEM). *P < 0.1, **P < 0.05, as determined by 2-tailed paired t tests.