Identifying Key Differences Between Responders vs. Non-Responders to Immune Checkpoint Blockade for Metastatic Osteosarcoma (mOS)

Abstract

Abstract Osteosarcoma is the most common childhood bone malignancy, with a sharp decline in survival rates upon metastasis. We have previously shown immune checkpoint blockade (ICB) of anti-CTLA-4/anti-PD-L1 for mice inoculated with a K7M2 metastatic osteosarcoma (mOS) cell line resulted in ~50% survival with complete tumor clearance, including recent analogous results upon replication of this treatment regimen. Differences in response rates to ICB are common among patients with the same malignancy across various cancers. Unlike inbred lab mice, human patients have diversity in genetic makeup and other factors, causing the discrepancy in ICB response to remain poorly understood. A culprit for these discrepancies is variance in circulating antibodies (Abs), which can indicate differences in disease presence, microbiome composition, or immune-modulating factors. Recent studies have characterized Ab patterns in sera by using microarrays with thousands of randomly sequenced peptides and incubating on them diluted sera. The Ab binding pattern on the microarray is termed an “immunosignature.” We have found that before inoculation with mOS or ICB, blood from mice displays distinct differences in immunosignatures between responders and non-responders, suggesting that the presence or absence of particular Abs may influence the outcome of ICB for mOS. Additionally, recent studies have discovered that ICB’s effectiveness can be associated with or even reliant on ICB recipients’ microbiome composition and that changes in microbiome composition can result in subsequent changes to circulating Abs. Here we analyze both differences in Ab composition and microbiome composition, highlighting their impact on ICB efficacy for mOS. Funding support for this work has been provided by a grant through the Sarcoma Foundation of America (SFA). Additional funding support for this work has been provided by a grant through the Graduate and Professional Student Association (GPSA) at Arizona State University.