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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.

SUBMITTER: Baitsch L

PROVIDER: S-EPMC3104769 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Baitsch Lukas L Baumgaertner Petra P Devêvre Estelle E Raghav Sunil K SK Legat Amandine A Barba Leticia L Wieckowski Sébastien S Bouzourene Hanifa H Deplancke Bart B Romero Pedro P Rufer Nathalie N Speiser Daniel E DE

The Journal of clinical investigation 20110509 6

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 significa ...[more]

PMID: 21555851

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Project description:In chronic viral infections such as HIV-1, HBV and HCV, CD8+ T cells may become ”exhausted”, characterized by progressive functional deficiency. Recently, the underlying mechanisms have been characterized by molecular profiling of virus-specific CD8+ T cells. In contrast, only little is known of self/tumor-specific CD8+ T cells from cancer patients, likely because they are much more difficult to assess. For the first time, we determined the molecular profile of human tumor-specific CD8+ T cells, upon sorting of Melan-A/MART-1 specific T cells directly ex vivo from 19 melanoma patients after vaccination with peptide and CpG. For comparison, we sorted protective T cells specific for the two herpes viruses EBV and CMV. In peripheral blood, we found multiple features of functional effector T cells, with only small but nevertheless significant differences between the three T cell populations, resulting in clean clustering according to antigen specificity. In contrast, Melan-A/MART-1 specific T cells obtained from tumor-infiltrated lymph nodes (TILNs) expressed multiple genes associated with T cell exhaustion, compatible with the known functional deficiencies of T cells in melanoma metastases. We show that individual T cells simultaneously expressed multiple inhibitory receptors implied in functional impairment. Together, the data indicate that in circulation, human tumor-specific T cells have the potential to become competent effector cells. In the tumor environment, however, T cells are exhausted and fail to control malignant disease. Our novel resource data identify mechanisms of functional T cell deficiency in melanoma patients, providing a rational basis for the improvement of immune therapy. 52 samples were measured in two sets of experiments. 4 self/tumor-specific samples from blood were replicated between the first and second sets. Set 1 (32 samples, all from blood): 13 naive samples, 10 EBV-specific samples, 9 self/tumor-specific samples. Set 2 (20 samples): 7 CMV-specific samples from blood, 7 self/tumor-specific samples from TILN, 6 self/tumor-specific samples from blood.

Project description:In chronic viral infections such as HIV-1, HBV and HCV, CD8+ T cells may become M-bM-^@M-^]exhaustedM-bM-^@M-^], characterized by progressive functional deficiency. Recently, the underlying mechanisms have been characterized by molecular profiling of virus-specific CD8+ T cells. In contrast, only little is known of self/tumor-specific CD8+ T cells from cancer patients, likely because they are much more difficult to assess. For the first time, we determined the molecular profile of human tumor-specific CD8+ T cells, upon sorting of Melan-A/MART-1 specific T cells directly ex vivo from 19 melanoma patients after vaccination with peptide and CpG. For comparison, we sorted protective T cells specific for the two herpes viruses EBV and CMV. In peripheral blood, we found multiple features of functional effector T cells, with only small but nevertheless significant differences between the three T cell populations, resulting in clean clustering according to antigen specificity. In contrast, Melan-A/MART-1 specific T cells obtained from tumor-infiltrated lymph nodes (TILNs) expressed multiple genes associated with T cell exhaustion, compatible with the known functional deficiencies of T cells in melanoma metastases. We show that individual T cells simultaneously expressed multiple inhibitory receptors implied in functional impairment. Together, the data indicate that in circulation, human tumor-specific T cells have the potential to become competent effector cells. In the tumor environment, however, T cells are exhausted and fail to control malignant disease. Our novel resource data identify mechanisms of functional T cell deficiency in melanoma patients, providing a rational basis for the improvement of immune therapy. 52 samples were measured in two sets of experiments. 4 self/tumor-specific samples from blood were replicated between the first and second sets. Set 1 (32 samples, all from blood): 13 naive samples, 10 EBV-specific samples, 9 self/tumor-specific samples. Set 2 (20 samples): 7 CMV-specific samples from blood, 7 self/tumor-specific samples from TILN, 6 self/tumor-specific samples from blood.

Dataset Information

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

Publications

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

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