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

María E Rodríguez-Ruiz,Pedro Berraondo,Iñaki Etxeberria,Mariano Ponz-Sarvise,Tania Labiano,Ignacio Melero,Lina Mayorga,Mary Helen Barcelos-Hoff,Elixabet Bolaños,Felipe A Calvo,Inmaculada Rodríguez,Jose L Perez-Gracia,Arantza Azpilikueta,Benigno Barbes,Miguel F Sanmamed

doi:10.1158/1535-7163.mct-18-0558

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.

Highlights

The role of radiotherapy as a means to augment response to immunotherapy has been explored in preclinical models [1, 2] and is currently being studied in multiple clinical trials [3,4,5,6,7]
We showed that radiation abscopal effects can be readily demonstrated in mice bearing two subcutaneous tumors in opposite flanks in which one tumor lesion is irradiated using external beam [17] or brachytherapy [18] in combination with systemic immunostimulatory mAbs directed to CD137 and PD-1
In a previous article [17], we reported that mice bilaterally bearing MC38-derived tumors showed abscopal effects as a result of a combined radiation and immunotherapy regimen encompassing three 8 Gy doses of unilateral radiotherapy (24 Gy/8 Gy/dose; ref. 37) and three every other day doses of anti–PD-1 and anti-CD137mAbs [17]

Summary

Introduction

The role of radiotherapy as a means to augment response to immunotherapy has been explored in preclinical models [1, 2] and is currently being studied in multiple clinical trials [3,4,5,6,7]. The most interesting experiments are those in which radiation elicits efficacy outside the irradiation fields, the so-called abscopal effects. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Methods

Results

Conclusion