The role of extracellular matrix quality in the prediction of metastasis-induced skeletal fragility and response to immunotherapy

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Metastatic bone disease (MBD) is a frequent and fatal complication in patients with advanced solid malignancies. Immune checkpoint inhibitors (ICIs) such as programmed cell death protein-1 (PD-1) have revolutionized cancer therapy over the past decade; however, the positive impact of ICIs in MBD is attenuated due to some immune- related skeletal adverse events (irSAEs), including the formation of new bone lesions, increased bone resorption, and vertebral compression fractures. The dynamic and multidirectional interactions between bone, immune, and tumor cells (osteoimmuno-oncology, OIO) can alter bone extracellular matrix (ECM) quality, influence bone mechanical integrity, and affect response to therapy, but OIO is currently underexamined in MBD. Receptor activator of nuclear factor kappa-β (RANK) and its ligand (RANKL) may be considered as key orchestrators of OIO yet their role in the setting of ICIs remain unexplored. Metastatic prostate cancer (PCa) cells, bone-forming osteoblasts, and activated T-cells trigger osteolysis independently by producing RANKL which binds to RANK on bone-resorbing osteoclasts (OCs). We hypothesize that modulation of RANK/RANKL and PD-1 signaling in OIO may support T-cell activation while inhibiting osteoclastic activity, thereby decreasing risk for worsening bone ECM quality and mechanical integrity and produce synergistic anticancer efficacy. Thus, we will (1) Characterize the expression of OIO-related ECM biomarkers in metastatic human bone and develop a prognostic signature of bone fragility; and (2) Evaluate the effects of combined RANKL and PD-1 blockade on bone ECM quality, mechanical integrity, and anti-cancer efficacy in mouse models of PCa bone metastases (BM). Cadaveric human trabecular bone cores from the lumbar vertebrae containing osteolytic, osteosclerotic, and mixed metastatic lesions will be compressed to failure for measurements of bone mechanical properties. Based on the distribution of the failure loads of the lesions, an appropriate threshold will be selected to create a binary measure of bone fragility. OIO-related bone ECM biomarkers and their posttranslational modifications will be extracted from each lesion. Using mixed effects multinomial logistic regression models a minimum set of biomarkers that predict bone fragility will be obtained. We will further validate these OIO-based biomarkers in distinct models of osteolytic and osteosclerotic PCa BM and assess the efficacy of anti-RANKL in mitigating bone fragility in the setting of anti-PD1 therapy. The results of this study will extend the current understanding of the effects of metastases and its treatment on bone matrix quality and mechanical integrity. OIO-related ECM markers that regulate lesion heterogeneity and predict fragility will provide new molecular information of functional relevance that can drive translational efforts. Moreover, the mechanisms of immune-mediated bone remodeling and mitigation of bone fragility by combined blockade of RANKL and PD-1 can aid in risk-adapted selection for ongoing and subsequent therapies.