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 4

TNF-α expression in TILs correlates with total TNF-α expression in CRC tissue.

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TNF-α expression in TILs correlates with total TNF-α expression in CRC t...
(A–C) Proportions of TNF-α–positive TCs among TCs (A), among total tumor-infiltrating cells (B), and among all TNF-α–positive cells (C) in primary tumors (PT) or CRC metastases (M) of 36 patients with CRC. Each circle represents values from one patient. TNF-α expression in TCs is separately shown for CD8+, CD4+, and total CD3+ TCs. *P < 0.05, as determined by unpaired 2-tailed t test. Mean ± SEM. (D) In situ expression of TNF-α (red signal) by CD8+ TILs (green signal) in a representative CRC specimen, as shown by immunofluorescence analysis of cryopreserved tissue (original magnification, ×20). (E–H) Proportions of TNF-α–positive TCs among CD8+ (E) or CD4+ (G) TILs and of total CD8+ (F) or CD4+ (H) among all tumor-infiltrating cells compared with the proportions of TNF-α–positive TCs among all tumor-infiltrating cells. Circles represent individual data from 27 different primary tumors. Strength and significance of respective correlations are indicated by r2 and P values.