Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.
AuthorsDovedi, Simon J
Cheadle, Eleanor J
Illidge, Timothy M
AffiliationTargeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom. Simon.Dovedi@ics.manchester.ac.uk.
MetadataShow full item record
AbstractRadiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiotherapy delivered in combination with αPD-1 or αPD-L1 mAbs generated efficacious CD8(+) T-cell responses that improved local tumor control, long-term survival, and protection against tumor rechallenge. These favorable outcomes were associated with induction of a tumor antigen-specific memory immune response. Mechanistic investigations showed that IFNγ produced by CD8(+) T cells was responsible for mediating PD-L1 upregulation on tumor cells after delivery of fractionated radiotherapy. Scheduling of anti-PD-L1 mAb was important for therapeutic outcome, with concomitant but not sequential administration with fractionated radiotherapy required to improve survival. Taken together, our results reveal the mechanistic basis for an adaptive response by tumor cells that mediates resistance to fractionated radiotherapy and its treatment failure. With attention to scheduling, combination immunoradiotherapy with radiotherapy and PD-1/PD-L1 signaling blockade may offer an immediate strategy for clinical evaluation to improve treatment outcomes.
CitationAcquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. 2014, 74 (19):5458-68 Cancer Res
- Integrin α<sub>v</sub>β<sub>3</sub>-targeted radionuclide therapy combined with immune checkpoint blockade immunotherapy synergistically enhances anti-tumor efficacy.
- Authors: Chen H, Zhao L, Fu K, Lin Q, Wen X, Jacobson O, Sun L, Wu H, Zhang X, Guo Z, Lin Q, Chen X
- Issue date: 2019
- Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model.
- Authors: Suarez ER, Chang de K, Sun J, Sui J, Freeman GJ, Signoretti S, Zhu Q, Marasco WA
- Issue date: 2016 Jun 7
- TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
- Authors: Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE III, Koeppen H, Astarita JL, Cubas R, Jhunjhunwala S, Banchereau R, Yang Y, Guan Y, Chalouni C, Ziai J, Şenbabaoğlu Y, Santoro S, Sheinson D, Hung J, Giltnane JM, Pierce AA, Mesh K, Lianoglou S, Riegler J, Carano RAD, Eriksson P, Höglund M, Somarriba L, Halligan DL, van der Heijden MS, Loriot Y, Rosenberg JE, Fong L, Mellman I, Chen DS, Green M, Derleth C, Fine GD, Hegde PS, Bourgon R, Powles T
- Issue date: 2018 Feb 22
- Safety and efficacy of anti-PD-L1 therapy in the woodchuck model of HBV infection.
- Authors: Balsitis S, Gali V, Mason PJ, Chaniewski S, Levine SM, Wichroski MJ, Feulner M, Song Y, Granaldi K, Loy JK, Thompson CM, Lesniak JA, Brockus C, Kishnani N, Menne S, Cockett MI, Iyer R, Mason SW, Tenney DJ
- Issue date: 2018
- Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance.
- Authors: Zheng W, Skowron KB, Namm JP, Burnette B, Fernandez C, Arina A, Liang H, Spiotto MT, Posner MC, Fu YX, Weichselbaum RR
- Issue date: 2016 Jul 12