Tumor-reactive T cells play an important role in cancer immuno-surveillance. Applying the multimer technology, we report here an unexpected high frequency of Melan-A-specific CTL in a melanoma patient with progressive lymph node (LN) metastases, consisting of 18% and 12.8% of total peripheral blood and tumor-infiltrating CD8+ T cells, respectively. Melan-A-specific CTL revealed a high cytotoxic activity against allogeneic Melan-A-expressing target cells but failed to kill the autologous tumor cells. Loading of the tumor cells with Melan-A peptide reversed the resistance to killing, suggesting impaired function of the MHC class I Ag processing and presentation pathway. Mutations and/or down-regulation of the MHC class I heavy chain, the antigenic peptide TAP, and tapasin could be excluded. However, RT-PCR and immunohistochemical analysis revealed a deficiency of the immunoproteasomes low molecular weight protein (LMP)2 and LMP7 in the primary tumor cells, that affects the quantity and quality of generated T cell epitopes and might explain the resistance to killing. Overall, this is the first report of an extremely high frequency of tumor-specific CTL that exhibit competent T cell effector functions, but fail to lyse the autologous tumor cells. Immunotherapeutic approaches should not only focus on the induction of a robust anti-tumor immune response, but also have to target tumor immune escape mechanisms.
Authors and Affiliations
Department of Hematology/Oncology, University of Regensburg, Regensburg, Germany
N Meidenbauer, M Laumer, S Vogl, J Heymann, M Rehli, R Andreesen & A Mackensen
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital (CHUV), Lausanne, Switzerland
A Zippelius, MJ Pittet & P Romero
III. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany
Department of Pathology, University of Regensburg, Regensburg, Germany
Laboratory of Tumor Immunology, Division of Oncology, University Hospital of Geneva, Geneva, Switzerland
Meidenbauer, N., Zippelius, A., Pittet, M. et al. High frequency of functionally active Melan-A specific T cells in a patient with progressive immunoproteasome-deficient melanoma.
Cancer Cell Int4
(Suppl 1), S9 (2004). https://doi.org/10.1186/1475-2867-4-S1-S9