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Association of high CD4-positive T cell infiltration with mutations in HLA class II-regulatory genes in microsatellite-unstable colorectal cancer

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Abstract

Besides being expressed on professional antigen-presenting cells, HLA class II antigens are expressed on various tumors of non-lymphoid origin, including a subset of colorectal cancers (CRC). Information about the regulation of HLA class II antigen expression is important for a better understanding of their role in the interactions between tumor and immune cells. Whether lack of HLA class II antigen expression in tumors reflects the selective immune destruction of HLA class II antigen-expressing tumor cells is unknown. To address this question, we tested whether lack of HLA class II antigen expression in CRC was associated with immune cell infiltration. We selected microsatellite-unstable (MSI-H) CRC, because they show pronounced tumor antigen-specific immune responses and, in a subset of tumors, lack of HLA class II antigen expression due to mutations inactivating HLA class II-regulatory genes. We examined HLA class II antigen expression, mutations in regulatory genes, and CD4-positive T cell infiltration in 69 MSI-H CRC lesions. Mutations in RFX5, CIITA, and RFXAP were found in 13 (28.9 %), 3 (6.7 %), and 1 (2.2 %) out of 45 HLA class II antigen-negative tumors. CD4-positive tumor-infiltrating lymphocyte counts were significantly higher in HLA class II antigen-negative tumors harboring mutations in HLA class II-regulatory genes (107.4 T cells per 0.25 mm2) compared to tumors without mutations (55.5 T cells per 0.25 mm2, p = 0.008). Our results suggest that the outgrowth of tumor cells lacking HLA class II antigen expression due to mutations of regulatory genes is favored in an environment of dense CD4-positive T cell infiltration.

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Abbreviations

cMS:

Coding microsatellite

CRC:

Colorectal cancer

HE:

Hematoxylin and eosin

HLA:

Human leukocyte antigen

HNPCC:

Hereditary nonpolyposis colorectal cancer

IHC:

Immunohistochemistry

mAb:

Monoclonal antibody

MSI-H:

High-level microsatellite instability

PCR:

Polymerase chain reaction

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Acknowledgments

We are grateful to Nina Nelius, Beate Kuchenbuch and Petra Höfler for the excellent technical support they provided. This work was supported by the Public Health Service (PHS) Grants R01 CA110249 and R01 CA138188 (Soldano Ferrone), awarded by the National Cancer Institute and by a Grant of the Deutsche Forschungsgemeinschaft (German Research Foundation).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Author notes

  1. Eva-Maria Surmann

    Present address: Medical Research Council Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge, CB2 0XZ, UK

Authors and Affiliations

  1. Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Eva-Maria Surmann, Anita Y. Voigt, Sara Michel, Kathrin Bauer, Miriam Reuschenbach, Magnus von Knebel Doeberitz & Matthias Kloor

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

    Eva-Maria Surmann, Anita Y. Voigt, Sara Michel, Kathrin Bauer, Miriam Reuschenbach, Magnus von Knebel Doeberitz & Matthias Kloor

  3. Molecular Medicine Partnership Unit, University Hospital Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany

    Eva-Maria Surmann, Anita Y. Voigt, Sara Michel, Kathrin Bauer, Miriam Reuschenbach, Magnus von Knebel Doeberitz & Matthias Kloor

  4. Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany

    Anita Y. Voigt

  5. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Soldano Ferrone

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  1. Eva-Maria Surmann
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Correspondence to Matthias Kloor.

Additional information

Eva-Maria Surmann and Anita Y. Voigt have contributed equally to the manuscript.

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Surmann, EM., Voigt, A.Y., Michel, S. et al. Association of high CD4-positive T cell infiltration with mutations in HLA class II-regulatory genes in microsatellite-unstable colorectal cancer. Cancer Immunol Immunother 64, 357–366 (2015). https://doi.org/10.1007/s00262-014-1638-4

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  • DOI: https://doi.org/10.1007/s00262-014-1638-4

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