Programmed Cell Death Protein 1 and Programmed Death-Ligand 1 Signaling Modulate Bone Homeostasis and Progression of Breast Cancer Bone Metastasis Through Perturbation of the Bone Marrow Immune Compartment

Abstract

Immune checkpoint inhibitors (ICIs) have increased cancer patient survival by blocking immunoregulatory receptor-ligand interactions (e.g., programmed cell death protein 1 [PD-1] and programmed death-ligand 1 [PD-L1]), thereby enabling the immune system to detect and kill cancer cells. Unfortunately, patients treated with ICIs commonly develop immune related adverse events. We report that blockade of PD-1 signaling results in bone loss in male and female adult and aged mice and across the axial and appendicular skeleton. We also observed expansion of CD4+ and CD8+ T cell populations in the bone marrow following PD-1 blockade and found that these T cells are necessary for PD-1 blockade-induced bone loss. At a molecular level, we identified T cell-IFNγ and monocyte-CCR2 signaling to be necessary for PD-1 blockade-induced bone loss, but further studies are needed to determine specific interactions driving this phenotype. In addition to skeletal toxicities stemming from ICI therapy, patients with bone metastases have poor survival when treated with ICIs. This is an important clinical issue given that multiple tumors (e.g., breast, prostate, lung) have high rates of metastasis to bone, but few studies have investigated this phenomenon. Our data suggest that treatment timeline in relation to bone metastatic engraftment is a critical factor in ICI-related skeletal toxicities and metastatic clearance. In a murine breast cancer bone metastasis model, ICI therapy initiated prior to tumor dissemination to bone increases CD8+ memory T cells, preserves bone mass and decreases bone tumor burden; however, ICI therapy initiated after tumor dissemination to bone reduces T cell populations in the bone marrow and results in bone loss and decreased tumor clearance from bone. This work confirms the impact of ICIs on the skeleton and on bone metastatic outgrowth and sets the stage for future studies to identify therapeutic targets to improve skeletal health and bone metastatic response to ICIs.