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[Cancer Research 64, 2865-2873, April 15, 2004]
© 2004 American Association for Cancer Research

Immunology

Effector Function of Human Tumor-Specific CD8 T Cells in Melanoma Lesions: A State of Local Functional Tolerance

Alfred Zippelius1, Pascal Batard1, Verena Rubio-Godoy1, Gilles Bioley1, Danielle Liénard1,2, Ferdy Lejeune2, Donata Rimoldi3, Philippe Guillaume3, Norbert Meidenbauer4, Andreas Mackensen4, Nathalie Rufer5,6, Norbert Lubenow7, Daniel Speiser1, Jean-Charles Cerottini3,6, Pedro Romero1,6 and Mikaël J. Pittet1

1 Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research and 2 Multidisciplinary Oncology Center, University Hospital (Centre Hospitalier Universitaire Vaudois), Lausanne, Switzerland; 3 Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; 4 Department of Hematology/Oncology, University of Regensburg, Regensburg, Germany; 5 Swiss Institute for Experimental Cancer Research and 6 National Center of Competence in Research Program on Molecular Oncology, Epalinges, Switzerland; 7 Institute of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany

Although tumor-specific CD8 T-cell responses often develop in cancer patients, they rarely result in tumor eradication. We aimed at studying directly the functional efficacy of tumor-specific CD8 T cells at the site of immune attack. Tumor lesions in lymphoid and nonlymphoid tissues (metastatic lymph nodes and soft tissue/visceral metastases, respectively) were collected from stage III/IV melanoma patients and investigated for the presence and function of CD8 T cells specific for the tumor differentiation antigen Melan-A/MART-1. Comparative analysis was conducted with peripheral blood T cells. We provide evidence that in vivo-priming selects, within the available naive Melan-A/MART-1-specific CD8 T-cell repertoire, cells with high T-cell receptor avidity that can efficiently kill melanoma cells in vitro. In vivo, primed Melan-A/MART-1-specific CD8 T cells accumulate at high frequency in both lymphoid and nonlymphoid tumor lesions. Unexpectedly, however, whereas primed Melan-A/MART-1-specific CD8 T cells that circulate in the blood display robust inflammatory and cytotoxic functions, those that reside in tumor lesions (particularly in metastatic lymph nodes) are functionally tolerant. We show that both the lymph node and the tumor environments blunt T-cell effector functions and offer a rationale for the failure of tumor-specific responses to effectively counter tumor progression.




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