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Regressing and progressing metastatic lesions: resistance to immunotherapy is predetermined by irreversible HLA class I antigen alterations

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Abstract

Despite the significant efforts to enhance immune reactivity against malignancies the clinical effect of anti-tumor vaccines and cancer immunotherapy is still below expectations. Understanding of the possible causes of such poor clinical outcome has become very important for improvement of the existing cancer treatment modalities. In particular, the critical role of HLA class I antigens in the success of T cell based immunotherapy has led to a growing interest in investigating the expression and function of these molecules in metastatic cancer progression and, especially in response to immunotherapy. In this report, we illustrate that two types of metastatic lesions are commonly generated in response to immunotherapy according to the pattern of HLA class I expression. We found that metastatic lesions, that progress after immunotherapy have low level of HLA class I antigens, while the regressing lesions demonstrate significant upregulation of these molecules. Presumably, immunotherapy changes tumor microenvironment and creates an additional immune selection pressure on tumor cells. As a result, two subtypes of metastatic lesions arise from pre-existing malignant cells: (a) regressors, with upregulated HLA class I expression after therapy, and (b) progressors with resistance to immunotherapy and with low level of HLA class I. Tumor cells with reversible defects (soft lesions) respond to therapy by upregulation of HLA class I expression and regress, while tumor cells with structural irreversible defects (hard lesions) demonstrate resistance to immunostimulation, fail to upregulate HLA class I antigens and eventually progress. These two types of metastases appear independently of type of the immunotherapy used, either non-specific immunomodulators (cytokines or BCG) or autologous tumor vaccination. Similarly, we also detected two types of metastatic colonies in a mouse fibrosarcoma model after in vitro treatment with IFN-γ. One type of metastases characterized by upregulation of all MHC class I antigens and another type with partial IFN-γ resistance, namely with lack of expression of Ld-MHC class I molecule. Our observations may shed new light on the understanding of the mechanisms of tumor escape and might have implications for improvement of the efficacy of cancer immunotherapy.

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Acknowledgments

This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS), Red Genomica del Cancer (RETIC RD 06/0020), Plan Andaluz de Investigacion (Group CTS-143), Consejeria Andaluz de Salud (SAS), Proyecto de Excelencia de Consejeria de Innovacion (CTS-695), Proyecto de investigacion I+D (SAF 2007-63262) in Spain; and from the Integrated European Cancer Immunotherapy project (OJ2004/C158, 518234).

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Authors and Affiliations

  1. Departamento de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Avd. Fuerzas Armadas 2, 18014, Granada, Spain

    Natalia Aptsiauri, Rafael Carretero, Angel Garcia-Lora, Teresa Cabrera & Federico Garrido

  2. Departamento de Bioquímica, Biología Molecular III e Inmunologia, Facultad de Medicina, Universidad de Granada, Granada, Spain

    Rafael Carretero, Teresa Cabrera & Federico Garrido

  3. Neocodex, Departamento de Genomica Estructural, Sevilla, Spain

    Luis M. Real

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  1. Natalia Aptsiauri
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  2. Rafael Carretero
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  3. Angel Garcia-Lora
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  4. Luis M. Real
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  5. Teresa Cabrera
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  6. Federico Garrido
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Correspondence to Federico Garrido.

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This article is a symposium paper from the conference “Progress in vaccination against cancer 2007 (PIVAC 7)”, held in Stockholm, Sweden, on 10–11 September 2007.

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Aptsiauri, N., Carretero, R., Garcia-Lora, A. et al. Regressing and progressing metastatic lesions: resistance to immunotherapy is predetermined by irreversible HLA class I antigen alterations. Cancer Immunol Immunother 57, 1727–1733 (2008). https://doi.org/10.1007/s00262-008-0532-3

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  • DOI: https://doi.org/10.1007/s00262-008-0532-3

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