Blockade of receptor activator of NF-κB ligand (RANKL) enhanced the antitumor efficacy of PD-1 blockade and combination PD-1 and CTLA-4 blockade. Double and triple combination therapies controlled growth of multiple subcutaneous tumors (dependent on T cells and IFNγ) and decreased the frequency of lung metastases in mice with B16F10 melanoma or RM-1 prostate cancer (dependent on NK cells and IFNγ). Triple therapy enhanced the Th1 cytokine polyfunctionality of T cells. Relative to checkpoint blockade, concurrent or delayed RANKL blockade was most effective.
Receptor activator of NF-kappaB ligand (RANKL) and its receptor RANK, are members of the tumor necrosis factor and receptor superfamilies, respectively. Antibodies targeting RANKL have recently been evaluated in combination with anti-CTLA4 in case reports of human melanoma and mouse models of cancer. However, the efficacy of anti-RANKL in combination with antibodies targeting other immune checkpoint receptors such as PD1 has not been reported. In this study, we demonstrated that blockade of RANKL improves anti-metastatic activity of antibodies targeting PD1/PD-L1 and improves subcutaneous growth suppression in mouse models of melanoma, prostate and colon cancer. Suppression of experimental lung metastasis following combination anti-RANKL with anti-PD1 requires NK cells and IFN-gamma, whereas subcutaneous tumor growth suppression with this combination therapy is attenuated in the absence of T cells and IFN-gamma. Furthermore, addition of anti-RANKL to anti-PD1 and anti-CTLA4 resulted in superior anti-tumor responses, irrespective of the ability of anti-CTLA4 isotype to engage activating FcR, and concurrent or delayed RANKL blockade was most effective. Early-during-treatment assessment reveals this triple combination therapy compared to dual anti-PD1 and anti-CTLA4 combination therapy further increased the proportion of tumor-infiltrating CD4(+) and CD8(+) T cells that can produce both IFN-gamma and TNF. Finally, RANKL expression appears to identify tumor-specific CD8(+) T cells expressing higher levels of PD1 which can be modulated by anti-PD1. These data set the scene for clinical evaluation of denosumab use in patients receiving contemporary immune checkpoint blockade.
Author Info: (1) Department of Immunology, Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Division of Cancer Care Serv
Author Info: (1) Department of Immunology, Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Division of Cancer Care Services, Medical Oncology, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia. (2) Department of Immunology, Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Faculty of Medicine, University of Queensland, Herston, Queensland, Australia. (3) Department of Immunology, Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Department of Immunology, Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Faculty of Medicine, University of Queensland, Herston, Queensland, Australia. (4) Department of Immunology, Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. (5) Department of Immunology, Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Department of Immunology, Immuno-oncology Discovery Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. (6) Department of Immunology, Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Faculty of Medicine, University of Queensland, Herston, Queensland, Australia. (7) Department of Immunology, Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Faculty of Medicine, University of Queensland, Herston, Queensland, Australia.
