- [IMMUNOLOGY AND IMMUNOTHERAPY]
- [COMBINATION STRATEGIES FOR TRANSLATIONAL IMMUNOTHERAPY]
- [CYTOKINE-BASED THERAPEUTICS]
TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies
María E Rodríguez-Ruiz, Inmaculada Rodríguez, Lina Mayorga, Tania Labiano, Benigno Barbes, Iñaki Etxeberria, Mariano Ponz-Sarvise, Arantza Azpilikueta, Elixabet Bolaños, Miguel F Sanmamed, Pedro Berraondo, Felipe A Calvo, Mary Helen Barcelos-Hoff, Jose L Perez-Gracia, Ignacio Melero
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.
CITA DEL ARTÍCULO Mol Cancer Ther. 2019 Mar;18(3):621-631. doi: 10.1158/1535-7163.MCT-18-0558. Epub 2019 Jan 25.