Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients
Lukas Baitsch, … , Nathalie Rufer, Daniel E. Speiser
Lukas Baitsch, … , Nathalie Rufer, Daniel E. Speiser
Published June 1, 2011; First published May 9, 2011
Citation Information: J Clin Invest. 2011;121(6):2350-2360. https://doi.org/10.1172/JCI46102.
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Categories: Research Article Immunology

Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients

Abstract

In chronic viral infections, CD8+ T cells become functionally deficient and display multiple molecular alterations. In contrast, only little is known of self- and tumor-specific CD8+ T cells from mice and humans. Here we determined molecular profiles of tumor-specific CD8+ T cells from melanoma patients. In peripheral blood from patients vaccinated with CpG and the melanoma antigen Melan-A/MART-1 peptide, we found functional effector T cell populations, with only small but nevertheless significant differences in T cells specific for persistent herpesviruses (EBV and CMV). In contrast, Melan-A/MART-1–specific T cells isolated from metastases from patients with melanoma expressed a large variety of genes associated with T cell exhaustion. The identified exhaustion profile revealed extended molecular alterations. Our data demonstrate a remarkable coexistence of effector cells in circulation and exhausted cells in the tumor environment. Functional T cell impairment is mediated by inhibitory receptors and further molecular pathways, which represent potential targets for cancer therapy.

Authors

Lukas Baitsch, Petra Baumgaertner, Estelle Devêvre, Sunil K. Raghav, Amandine Legat, Leticia Barba, Sébastien Wieckowski, Hanifa Bouzourene, Bart Deplancke, Pedro Romero, Nathalie Rufer, Daniel E. Speiser

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Figure 5

Exhaustion profile of tumor-specific T cells in situ.

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Exhaustion profile of tumor-specific T cells in situ. (A) IFN-γ producti...
(A) IFN-γ production by tumor-specific T cells from the circulation (blood; n = 6) or TILN (n = 8) after 4-hour antigen stimulation. Whiskers in box plots indicate maximum and minimum values measured. Cross indicates the mean, while line indicates the median. **P < 0.01. (B) Differential gene expression by tumor-specific T cells isolated from blood versus TILN, as illustrated by a volcano plot for all gene probes. (C) Two-way hierarchical clustering based on the identified 346 genes separating all blood-derived tumor-specific T cells from their TILN counterparts. Red indicates overexpression and blue underexpression relative to the mean. Each row represents 1 gene and each column 1 1,000-cell sample from 1 patient. (D) Log fold change between tumor-specific T cells from blood versus TILN; data from microarrays (blue bars) and qPCR (red bars). Positive and negative values indicate overexpression in tumor-specific T cells from TILN and from blood, respectively. Mean ± SEM. (E) Relative overexpression of GO terms associated with the identified genes, calculated as described in Methods. (F) Enrichment of the gene set described for exhausted T cells (2) in TILN-derived tumor-specific T cells, relative to their blood-derived counterparts. The positions of inhibitory receptors found in this gene set on the rank-ordered gene list are indicated. A position to the left indicates enrichment in TILN-derived cells, a position to the right enrichment in blood-derived cells.