Journal article

Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8 T cells

Clara Gomez-Aleza, Bastien Nguyen, Guillermo Yoldi, Marina Ciscar, Alexandra Barranco, Enrique Hernandez-Jimenez, Marion Maetens, Roberto Salgado, Maria Zafeiroglou, Pasquale Pellegrini, David Venet, Soizic Garaud, Eva M Trinidad, Sandra Benitez, Peter Vuylsteke, Laura Polastro, Hans Wildiers, Philippe Simon, Geoffrey Lindeman, Denis Larsimont Show all

Nature Communications | NATURE RESEARCH | Published : 2020

Abstract

Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8+ T cells, and reduces macrophage and neutrophil infiltration. CD8+ T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-..

View full abstract

Grants

Awarded by MICINN


Awarded by European Research Council (ERC) under the European Union


Awarded by Breast Cancer Research Foundation (BCRF)


Awarded by Cancer Center Support Grant of the National Institutes of Health


Funding Acknowledgements

We thank the patients who contributed to this study and acknowledge the clinical staff for their dedication. The D-BEYOND clinical trial was sponsored by Jules Bordet Institute, which was responsible for the management of the study. This work was supported by grants to E. Gonzalez-Suarez by MICINN (SAF2014-55997-R, SAF201786117-R) co-funded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 682935), and Fundacio La Marato de TV3. We thank CERCA Programme/Generalitat de Catalunya for institutional support. P.P. and S.B. were and A.B. is recipient of a predoctoral grant from the MICINN. We are grateful to William C. Dougall and AMGEN, Inc. for supporting the design of the D-BEYOND trial and providing RANKL, RANK-Fc reagents, and RANK-/-mice. We thank the IDIBELL Animal Facility for their assistance with mouse colonies, Esther Castano and the scientific services of the University of Barcelona for their assistance with FACS analyses, and P. Gonzalez-Santamaria, G PerezChacon, and M Jimenez for critical reading of the manuscript. C.S. and B.N. are supported by the National Fund for Research (FNRS) and Televie. R.S. is supported by a grant from the Breast Cancer Research Foundation (BCRF), grant number 17-194. This work was also supported in part by the Cancer Center Support Grant of the National Institutes of Health (Grant Number P30CA008748). We thank Samira Majjaj and Delphine Vincent for technical assistance. We extend gratitude to the patients who participated in the D-BEYOND study. This clinical study has been supported by research funding from Amgen.