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T cell responses against microsatellite instability-induced frameshift peptides and influence of regulatory T cells in colorectal cancer

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Abstract

High-level microsatellite-unstable (MSI-H) colorectal carcinomas (CRC) represent a distinct subtype of tumors commonly characterized by dense infiltration with cytotoxic T cells, most likely due to expression of MSI-H-related frameshift peptides (FSP). The contribution of FSP and classical antigens like MUC1 and CEA to the cellular immune response against MSI-H CRC had not been analyzed so far. We analyzed tumor-infiltrating and peripheral T cells from MSI-H (n = 4 and n = 14, respectively) and microsatellite-stable (MSS) tumor patients (n = 26 and n = 17) using interferon gamma ELISpot assays. Responses against 4 FSP antigens and peptides derived from MUC1 to CEA were compared with and without depletion of regulatory T cells, and the results were related to the presence of the respective antigens in tumor tissue. Preexisting FSP-specific T cell responses were detected in all (4 out of 4) tumor-infiltrating and in the majority (10 out of 14) of peripheral T cell samples from MSI-H CRC patients, but rarely observed in MSS CRC patients. Preexisting T cell responses in MSI-H CRC patients were significantly more frequently directed against FSP tested in the present study than against peptides derived from classical antigens MUC1 or CEA (p = 0.049). Depletion of regulatory T cells increased the frequency of effector T cell responses specific for MUC1/CEA-derived peptides and, to a lesser extent, T cell responses specific for FSP. Our data suggest that the analyzed FSP may represent an immunologically relevant pool of antigens capable of eliciting antitumoral effector T cell responses.

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Abbreviations

Bc:

B lymphocytes

CRC:

Colorectal carcinoma

FSP:

Frameshift-derived peptides

IFN:

Interferon

MSI-H:

High-level microsatellite instability

MSS:

Microsatellite stable

PBMC:

Peripheral blood mononuclear cells

TIL:

Tumor-infiltrating lymphocytes

Treg cells:

Regulatory T cells

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Acknowledgments

The excellent technical assistance of Beate Kuchenbuch, Petra Höfler and Daniel Baumgärtner is gratefully acknowledged. The study was funded in part by the Deutsche Krebshilfe (German Cancer Aid) and the Deutsche Forschungsgemeinschaft (KFO 227).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Germany

    Kathrin Bauer, Nina Nelius, Miriam Reuschenbach, Jürgen Kopitz, Magnus von Knebel Doeberitz & Matthias Kloor

  2. Cooperation Unit Applied Tumor Biology, DKFZ (German Cancer Research Center), Heidelberg, Germany

    Kathrin Bauer, Nina Nelius, Miriam Reuschenbach, Jürgen Kopitz, Magnus von Knebel Doeberitz & Matthias Kloor

  3. Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany

    Moritz Koch, Jürgen Weitz, Gunnar Steinert & Mirjam Tariverdian

  4. Department of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Philipp Beckhove

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  1. Kathrin Bauer
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  2. Nina Nelius
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Correspondence to Kathrin Bauer.

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Bauer, K., Nelius, N., Reuschenbach, M. et al. T cell responses against microsatellite instability-induced frameshift peptides and influence of regulatory T cells in colorectal cancer. Cancer Immunol Immunother 62, 27–37 (2013). https://doi.org/10.1007/s00262-012-1303-8

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  • DOI: https://doi.org/10.1007/s00262-012-1303-8

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