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Mol Cancer Ther. 2019 Mar;18(3):621-631. doi: 10.1158/1535-7163.MCT-18-0558. Epub 2019 Jan 25.

TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies.

Author information

1
Department of Oncology, University of Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain. imelero@unav.es mrruiz@unav.es.
2
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
3
Department of Cellular Therapy, University of Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
4
Department of Oncology, University of Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
5
Department of Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain.
6
Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
7
Department of Radiation Oncology, University of California, San Francisco, San Francisco, California.
#
Contributed equally

Abstract

Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effects against syngeneic transplanted murine tumors up to a certain tumor size. Knowing that TGFβ expression or activation increases in irradiated tissues, we tested whether TGFβ blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination. Indeed, TGFβ blockade with 1D11, a TGFβ-neutralizing mAb, markedly enhanced abscopal effects and overall treatment efficacy against subcutaneous tumors of either 4T1 breast cancer cells or large MC38 colorectal tumors. Increases in CD8 T cells infiltrating the nonirradiated lesion were documented upon combined treatment, which intensely expressed Granzyme-B as an indicator of cytotoxic effector capability. Interestingly, tumor tissue but not healthy tissue irradiation results in the presence of higher concentrations of TGFβ in the nonirradiated contralateral tumor that showed smad2/3 phosphorylation increases in infiltrating CD8 T cells. In conclusion, radiotherapy-induced TGFβ hampers abscopal efficacy even upon combination with a potent immunotherapy regimen. Therefore, TGFβ blockade in combination with radioimmunotherapy results in greater efficacy.

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