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 2

Increased TNF-α content in CRC tissue of patients with TA-reactive TC responses.

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Increased TNF-α content in CRC tissue of patients with TA-reactive TC re...
(A) IFN-γ ELISPOT from one representative patient with CRC (n = 3), showing IFN-γ spot numbers (triplicates) from wells containing DCs pulsed with PBMC lysate (PB-L), normal colonic mucosa lysate (Muc-L), both autologous or human IgG (IgG) as controls (white bars), or with autologous tumor lysate (Tu-L, black bar). (B) Proportions of patients with CRC showing or lacking tumor-reactive (TA-reactive) TCs in peripheral blood or bone marrow (n = 26). (C) Absolute TNF-α protein concentration in CRC tumors from patients containing (n = 11) or lacking (n = 15) tumor-reactive TCs in peripheral blood or bone marrow. Circles indicate values from individual patients. (D) Expression of IFN-γ and TNF-α in gated CD4+ T and CD8+ TCs in PBTCs stimulated with TA or with human IgG, as determined by cytokine capture assay. Data from one representative patient with CRC (n = 7) is shown. Numbers in dot plots indicate the proportion (%) of cytokine-expressing cells among gated cells. (E) Proportion of cytokine-secreting TA-reactive CD4+ and CD8+ TCs in the blood of 7 patients with CRC. Each symbol represents data from an individual patient with the value of the background reactivity (against IgG) subtracted. (F) Proportion of cytokine-secreting TCs after stimulation with TA or IgG in the blood and bone marrow of 4 patients with CRC. *P < 0.05, as determined by unpaired 2-tailed t test; mean ± SEM.