1. Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells
- Author
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Thierry Walzer, Josef M. Penninger, Peter Vuylsteke, Gert Van den Eynden, Bastien Nguyen, Eva González-Suárez, Sherene Loi, Soizic Garaud, C. Velghe, David Venet, Françoise Rothé, Purificación Muñoz, Lourdes Planelles, Enrique Hernández-Jiménez, Philippe Simon, Hans Wildiers, Eva M. Trinidad, Sandra Benítez, Hatem A. Azim, Guillermo Yoldi, Christos Sotiriou, Roberto Salgado, Geoffrey J. Lindeman, Maria Zafeiroglou, Marina Ciscar, Alexandra Barranco, Stefan Michiels, Clara Gómez-Aleza, Martine Piccart, Laura Polastro, Karen Willard-Gallo, Pasquale Pellegrini, Marion Maetens, Denis Larsimont, Institut Jules Bordet, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), European Research Council, Fundación La Marató TV3, National Fund for Research (Francia), Breast Cancer Research Foundation, Jules Bordet Institute, European Regional Development Fund (ERDF/FEDER), European Research Council (ERC), Fundacio La Marato de TV3, National Fund for Research (FNRS), and Breast Cancer Research Foundation (BCRF)
- Subjects
0301 basic medicine ,Chemokines -- metabolism ,Chemokine ,Neutrophils ,medicine.medical_treatment ,General Physics and Astronomy ,Cancer immunotherapy ,CD8-Positive T-Lymphocytes ,0302 clinical medicine ,Breast cancer ,Cytotoxic T cell ,Myeloid Cells ,Receptor Activator of Nuclear Factor-kappa B -- metabolism ,Multidisciplinary ,biology ,Receptor Activator of Nuclear Factor-kappa B ,Sciences bio-médicales et agricoles ,Middle Aged ,3. Good health ,Inflammation Mediators -- metabolism ,RANKL ,030220 oncology & carcinogenesis ,Female ,Immunotherapy ,Chemokines ,Denosumab ,Inflammation Mediators ,Signal Transduction ,Adult ,Science ,RANK Ligand -- blood -- metabolism ,Breast Neoplasms ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Article ,CD8-Positive T-Lymphocytes -- immunology ,03 medical and health sciences ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Denosumab -- pharmacology -- therapeutic use ,Breast Neoplasms -- blood -- drug therapy -- immunology -- pathology ,Neoplasm Staging ,Immunosuppression Therapy ,Myeloid Cells -- immunology ,business.industry ,Tumor-infiltrating lymphocytes ,RANK Ligand ,Immunity ,Médecine pathologie humaine ,General Chemistry ,Cancérologie ,Mice, Inbred C57BL ,030104 developmental biology ,Neutrophils -- immunology ,biology.protein ,Cancer research ,business ,Lymphocytes, Tumor-Infiltrating -- immunology ,Immunosuppression - 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-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8+ T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy., info:eu-repo/semantics/published
- Published
- 2020