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TGF-alpha as a candidate tumor antigen for renal cell carcinomas

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Abstract

Objectives

Patients with renal cell carcinomas (RCC) have few treatment options, underscoring the importance of developing new approaches such as immunotherapy. However, few tumor associated antigens (TAA), which can be targeted by immunotherapy, have been identified for this type of cancer. von Hippel-Lindau clear cell RCC (VHL−/−RCC) are characterized by mutations in the VHL tumor suppressor gene. Loss of VHL function causes the overexpression of transforming growth factor (TGF)-α, leading us to hypothesize that TGF-α could be a potential TAA for immunotherapy of kidney cancer, which was evaluated in this study.

Methods and results

We first confirmed the absent or weak expression of TGF-α in important normal tissues as well as its overexpression in 61% of renal tumors in comparison to autologous normal kidney tissues. In addition, we demonstrated the immunogenicity of TGF-α, by expanding many T cell lines specific for certain TGF-α peptides or the mature TGF-α protein, when presented by major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells. Interestingly, some of these TGF-α-specific T cells were polyfunctionals and secreted IFN-γ, TNF-α and IL-2.

Conclusion

We have shown that TGF-α is a valid candidate TAA, which should allow the development of a targeted immunotherapy.

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Abbreviations

APC:

Antigen presenting cells

CCRCC:

Clear cell renal cell carcinoma

CD40-B:

CD40-activated B lymphocytes

EBV-B:

Immortalized B lymphocytes with the Epstein–Barr virus

GM-CSF:

Granulocyte/macrophage-colony stimulating factor

HIF:

Hypoxia inducible factor

HLA:

Human leukocyte antigen

IFN-γ:

Interferon-γ

MHC:

Major histocompatibility complex

PBMC:

Peripheral blood mononuclear cells

TAA:

Tumor-associated antigen

TIL:

Tumor-infiltrating lymphocytes

TGF-α:

Transforming growth factor-α

VHL:

von Hippel-Lindau

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Acknowledgments

The editorial assistance of Ovid Da Silva, Support Office, Research Centre, CHUM, is acknowledged. We also thank Robert Boileau for statistical analyses. N.A. was supported by a Senior Research Fellowship from the Canadian Institutes of Health Research and now holds a Donald Paty Career Development Award from the Multiple Sclerosis Society of Canada and a Chercheur-Boursier from the Fonds de la Recherche en Santé du Québec. R.L. is the recipient of a “Fond pour la recherche en santé du Québec” scholarship.

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The authors have nothing to disclose.

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Authors and Affiliations

  1. Department of Medicine, CRCHUM-Hôpital Notre-Dame, Université de Montréal, Montreal, Canada

    Sandy Pelletier, Nathalie Arbour & Réjean Lapointe

  2. Institut du Cancer de Montreal, Montreal, QC, Canada

    Sandy Pelletier & Réjean Lapointe

  3. McGill University Health Centre, Montreal General Hospital, Montreal, QC, Canada

    Simon Tanguay

  4. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

    Stephen Lee & Lakshman Gunaratnam

  5. Centre de Recherche, CRCHUM-Hôpital Notre-Dame, Pavillon De Sève, Y-5605, 2099 rue Alexandre De Sève, Montreal, QC, H2L 4M1, Canada

    Réjean Lapointe

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  1. Sandy Pelletier
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Correspondence to Réjean Lapointe.

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Pelletier, S., Tanguay, S., Lee, S. et al. TGF-alpha as a candidate tumor antigen for renal cell carcinomas. Cancer Immunol Immunother 58, 1207–1218 (2009). https://doi.org/10.1007/s00262-008-0630-2

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  • DOI: https://doi.org/10.1007/s00262-008-0630-2

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