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