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 May 9, 2011
Citation Information: J Clin Invest. 2011;121(6):2350-2360. https://doi.org/10.1172/JCI46102.
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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 6

Multi-tetramer staining assessing coexpression of inhibitory receptors.

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Multi-tetramer staining assessing coexpression of inhibitory receptors. ...
(A) Staining with tetramers binding to EBV- (PE–Texas Red), Melan-A/MART-1– (APC–eFluor 780), or CMV- (PE–Texas Red and APC–eFluor 780) specific T cells (labeling tetramers with 2 instead of 1 fluorochrome identifies larger numbers of epitope-specific T cell populations than the number of fluorescence channels used). T cells were analyzed for coexpression of 7 inhibitory receptors: KLRG-1 (Alexa Fluor 488), TIM-3 (PE), PD-1 (PerCP-eFluor710), and CD160 (Alexa Fluor 647), or LAG-3 (FITC), 2B4 (PE-Cy5.5), and CTLA-4 (APC). (B) Expression of 7 different inhibitory receptors. Histograms of a representative sample are gated on CD8+ tetramer+ cells. Box plots summarize the data of all patients analyzed (EBV, n = 16; CMV, n = 6; Melan-A blood, n = 10, except for CTLA-4, n = 3; Melan-A TILN, n = 8–9). Whiskers in box plots indicate the maximum and minimum values measured. Cross indicates the mean, while line indicates the median. *P < 0.05; #P < 0.01; §P < 0.001. (C) Coexpression of 0 to 4 and 0 to 3 inhibitory receptors was analyzed with SPICE (48).