Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells
Autor: | 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 |
---|---|
Přispěvatelé: | 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), Breast Cancer Research Foundation (BCRF) |
Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
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 |
Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-18 (2020) Nature Communications Nature communications, 11 (1 Repisalud Instituto de Salud Carlos III (ISCIII) |
ISSN: | 2041-1723 |
Popis: | 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 |
Databáze: | OpenAIRE |
Externí odkaz: |