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Can local radiotherapy and IL-12 synergise to overcome the immunosuppressive tumor microenvironment and allow “in situ tumor vaccination”?

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Abstract

The abscopal effect, which is the spontaneous regression of tumors or metastases outside the radiation field, occurs rarely in cancer patients. Interestingly, radiotherapy (RT) triggers an immunogenic cell death (ICD) that is able to generate tumor-specific cytotoxic CD8+ T cells that are efficient in killing cancer cells. The key question is: why is this “abscopal effect” so uncommon in cancer patients treated with RT? Most probably, the main reason may be related to the highly immunosuppressive tumor microenvironment of well-established tumors that constantly antagonizes the anti-tumor immune responses triggered by RT. In this case, additional or combinatorial immunotherapy is needed to attenuate these immunosuppressive networks and, therefore, substantially increases the efficacy of RT. Here, we describe a potentially promising synergistic radio-immunotherapy “in situ tumor vaccination” protocol by antagonizing the tumor-immunosuppressive microenvironment with a combinatorial approach using local RT and IL-12-based TH1 response augmentation.

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Abbreviations

ATP:

Adenosine triphosphate

CRT:

Calreticulin

CTLA4:

Cytotoxic-T lymphocyte-associated antigen 4

CXCL10/IP-10:

Interferon-inducible protein 10

CXCL9/Mig:

Monokine induced by interferon gamma

DAMPs:

Damage-associated molecular patterns

DCs:

Dendritic cells

ESCC:

Esophageal squamous cell carcinoma

GB:

Glioblastoma

HMGB1:

High mobility group protein B1

ICD:

Immunogenic cell death

iNOS/M1:

Macrophage M1 inducible nitric oxide synthase

MDCSs:

Myeloid-derived suppressor cells

NSCLC:

Non-small cell lung cancer

PD1:

Programmed cell death protein 1

RT:

Radiotherapy

TGF-β:

Transforming growth factor-β

TH1:

Type I T helper

TILs:

Tumor-infiltrating lymphocytes

TLR4:

Toll like receptor 4

Treg:

Regulatory T cell(s)

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Acknowledgements

This work was supported by a Grant from INSERM (Institut National de la santé et de la recherche médicale) and faculté de médécine Paris VI.

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Authors and Affiliations

  1. Département d’Oncologie, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 46, 1011, Lausanne, Switzerland

    Gaël Deplanque, Keyvan Shabafrouz & Michel Obeid

  2. Faculté de Médecine Pitié-Salpêtrière, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie, 91 Boulevard de l’Hôpital, 75013, Paris, France

    Michel Obeid

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  1. Gaël Deplanque
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  3. Michel Obeid
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Correspondence to Michel Obeid.

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This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the European Union “European directive 86/609/EEC” and the French National Institutes of Health. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Pierre et Marie Curie, Paris, France (Permit Number: A751301).

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Deplanque, G., Shabafrouz, K. & Obeid, M. Can local radiotherapy and IL-12 synergise to overcome the immunosuppressive tumor microenvironment and allow “in situ tumor vaccination”?. Cancer Immunol Immunother 66, 833–840 (2017). https://doi.org/10.1007/s00262-017-2000-4

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