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 4

Circulating tumor-specific T cells are late-differentiated effector cells, resembling CMV-specific T cells.

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Circulating tumor-specific T cells are late-differentiated effector cell...
(A) Gene set enrichment of genes describing effector cells (see Figure 2D). Genes to the left and right of the rank-ordered list are enriched in tumor- and EBV-specific T cells, respectively. (B) Gene set enrichment of genes describing memory cells (2). Genes to the left and right of the rank-ordered list are enriched in tumor- and EBV-specific T cells, respectively. (C) No differences were found between Melan-A/MART-1– and CMV-specific T cells, demonstrated by a gene set defining effector cell–related genes (31). (D) Intracellular staining of naive and antigen-specific T cells. Top panels show 1 representative example; below are the combined results of all samples (EBV and CMV, n = 5; Melan-A, n = 15; naive, n = 25). Data of EBV- and CMV-specific T cells are from healthy donors, while data of tumor-specific T cells are from patients. ***P < 0.001. Whiskers in box plots indicate maximum and minimum values measured. Line indicates the median.