Exploring the role of the receptor activator of nuclear factor-κB (RANK) pathway in breast cancer, Aleza, Nguyen, and Yoldi et al. demonstrated in the PyMT mammary tumor model that blocking the tumor cell RANK pathway increases CD8+ T cell infiltration and reduces immunosuppressive neutrophil accumulation in tumors. Anti-RANKL antibody therapy results in improved survival, which is enhanced by ICB. In a clinical trial of an anti-RANKL Ab in pre-surgical breast cancer, similar favorable changes in T cell infiltration were observed, and serum (solRANKL), IHC (Treg), and biopsy (RNASeq) prognostic markers were identified.
Contributed by Ed Fritsch
ABSTRACT: Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-_B (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.
Author Info: (1) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. (2) Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Universit
Author Info: (1) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. (2) Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. Marie-Jose and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. (3) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. (4) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (5) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (6) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. (7) Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (8) Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. Department of Pathology, GZA-ZNA Ziekenhuizen, Antwerp, Belgium. (9) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. (10) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. (11) Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (12) Molecular Immunology Unit, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (13) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. (14) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. (15) Department of Medical Oncology, Universit Catholique de Louvain, CHU UCL, Namur, site Sainte-Elisabeth, Namur, Belgium. (16) Department of Medical Oncology, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (17) Department of Oncology, KU Leuven-University of Leuven, Leuven, Belgium. (18) Department of Obstetrics and Gynaecology, Erasme, Universit Libre de Bruxelles, Brussels, Belgium. (19) Peter MacCallum Cancer Centre, The Walter and Eliza Hall Institute of Medical Research and The Royal Melbourne Hospital, Melbourne, VIC, Australia. (20) Department of Pathology, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (21) Molecular Immunology Unit, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (22) Clinical Trial Supporting Unit, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (23) Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (24) Molecular Immunology Unit, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (25) Service de Biostatistique et D'Epidmiologie, Gustave Roussy, CESP, U1018, Universit Paris-Sud, Facult de Mdcine, Universit Paris-Saclay, Villejuif, France. (26) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. (27) Centre International de Recherche en Infectiologie, CIRI, Inserm U1111, CNRS, Universit Claude Bernard, Lyon, France. (28) BiOncotech Therapeutics, Parc Cientific Universitat, Valencia, Spain. (29) Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. (30) Division of Hematology/Oncology, Department of Medicine, American University of Beirut, Beirut, Lebanon. (31) Peter MacCallum Cancer Centre, The Walter and Eliza Hall Institute of Medical Research and The Royal Melbourne Hospital, Melbourne, VIC, Australia. (32) Department of Medical Oncology, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. (33) Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. christos.sotiriou@bordet.be. Department of Medical Oncology, Institut Jules Bordet, Universit Libre de Bruxelles, Brussels, Belgium. christos.sotiriou@bordet.be. (34) Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain. egonzalez@cnio.es. Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. egonzalez@cnio.es.
