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

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.

Grant Number: 1R21CA284159-01
NIH Institute/Center: NIH
Principal Investigator: Stacyann Bailey