Journal Article
. 2018 Jun; 7(6):e1431088.
doi: 10.1080/2162402X.2018.1431088.

RANKL blockade improves efficacy of PD1-PD-L1 blockade or dual PD1-PD-L1 and CTLA4 blockade in mouse models of cancer

Elizabeth Ahern 1 Heidi Harjunpää 2 Jake S O'Donnell 1 Stacey Allen 2 William C Dougall 1 Michele W L Teng 2 Mark J Smyth 1 
  • PMID: 29872559
  •     50 References
  •     37 citations


Receptor activator of NF-κB 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-γ, whereas subcutaneous tumor growth suppression with this combination therapy is attenuated in the absence of T cells and IFN-γ. 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-γ 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.

Keywords: CD8+ T cells; RANK; RANKL; metastasis; tumors.

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