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Immunotherapy eradicates metastases with reversible defects in MHC class I expression

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Abstract

Tumor or metastatic cells lose MHC class I (MHC-I) expression during cancer progression as an escape mechanism from immune surveillance. These defects in MHC-I may be reversible by cytokines or different agents (soft lesions) or irreversible due to structural defects (hard lesions). The nature of these MHC-I alterations might determine the success or failure of immunotherapy treatments. In this study, we have used an MHC-I-positive murine fibrosarcoma tumor clone, GR9-A7, which generates multiple lung and lymph node metastases with reversible MHC-I alterations after treatment with IFN-γ. Four different antitumor treatments were carried out after primary tumor excision to determine their capacity to inhibit spontaneous metastatic colonization of the GR9-A7 tumor clone. We found that 2 different immunotherapy protocols (CpG plus autologous irradiated-GR9-A7 cells and protein-bound polysaccharide K (PSK) and 1 chemoimmunotherapy (docetaxel plus PSK) induced eradication of metastases. In contrast, chemotherapy with docetaxel alone produced only partial reduction in the number of metastases. Flow cytometric analysis of lymphocyte populations showed an immunosuppression in GR9-A7 tumor-bearing host, which could be reverted by immunotherapy treatments. Our results suggest that irreversible or reversible MHC-I alterations in tumor target cells may determine its progression or regression independently of the type of immunotherapy used.

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Abbreviations

MHC-I:

Major histocompatibility complex class I

H-2:

Mouse leukocyte antigen

HLA:

Human leukocyte antigen

PSK:

Protein-bound polysaccharide K

BCG:

Bacillus of Calmette-Guérin

MCA:

Methylcholanthrene

PMs:

Pulmonary metastases

LNMs:

Lymph node metastases

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Acknowledgments

The authors thank I. Linares and E. Arias for technical assistance and staff of the Departments of Hospital Pharmacy and Radiotherapeutic Oncology of the Virgen de las Nieves University Hospital for their collaboration. They also thank Dr. Natalia Aptsiauri for helpful discussion and Richard Davies for editorial assistance. C. Garrido was supported by the MEC (FPU, 1631) and A.M. García-Lora by FIS-Research Contract CP03/0111 and Stabilization Contract of Fundación Progreso y Salud. This study was partially funded by grants from the FIS (CP03/0111; PI 08/1265; RTICC, RETIC RD 06/020), Consejería de Salud and PAI (Group CTS-143 and projects CTS-695 and CTS-3952) from the Junta de Andalucía in Spain; by the ENACT project (LSHC-CT-2004-503306) and by the Cancer Immunotherapy project (OJ 2004/c158, 18234) of the European Community; and by Kureha Chemical Industry, Tokyo, Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Departamento De Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain

    Cristina Garrido & Federico Garrido

  2. Servicio de Análisis Clínicos and Inmunología, Hospital Universitario Virgen de las Nieves, Av. Fuerzas Armadas 2, 18014, Granada, Spain

    Cristina Garrido, Irene Romero, Enrique Berruguilla, Angel García-Lora & Federico Garrido

  3. Servicio de Farmacia, Hospital Universitario Virgen de las Nieves, Granada, Spain

    Bárbara Cancela

  4. Departamento de Ciencias de la Salud, Universidad de Jaén, Jaén, Spain

    Ignacio Algarra

  5. Unidad de Investigación, Hospital Universitario Virgen de las Nieves, Granada, Spain

    Antonia Collado

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  1. Cristina Garrido
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  2. Irene Romero
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  3. Enrique Berruguilla
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  4. Bárbara Cancela
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  7. Angel García-Lora
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  8. Federico Garrido
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Correspondence to Angel García-Lora or Federico Garrido.

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Garrido, C., Romero, I., Berruguilla, E. et al. Immunotherapy eradicates metastases with reversible defects in MHC class I expression. Cancer Immunol Immunother 60, 1257–1268 (2011). https://doi.org/10.1007/s00262-011-1027-1

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  • DOI: https://doi.org/10.1007/s00262-011-1027-1

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