Targeting Epigenetic Vulnerabilities in Osteosarcoma to Enhanced Immunotherapy

Osteosarcoma (OS) is the most common bone sarcoma in children and the 8th most common childhood cancer. Currently, limited immunotherapies are available for OS due to two main obstacles: immunosuppressive tumor microenvironment and secondary immune toxicity. OS resistance mechanisms to immunotherapy can largely be categorized into tumor cell-intrinsic and extrinsic mechanisms. Tumor cell-intrinsic mechanisms include downregulation of major histocompatibility complex class I (MHC-I) molecules, which reduces tumor immunogenicity and enhances immune evasion. Although epigenetic dysregulation plays a crucial role in immune evasion by downregulating tumor antigen presentation in several other solid tumors, epigenetic modifiers, specifically implicated in OS immune evasion, remain largely to be determined. Tumor cell-extrinsic mechanisms involve the elevated expression of the innate immune checkpoint molecule, CD47, and PD-L1. In addition, tumor acidification within the OS TME, deactivates immunostimulatory cytokines, such as interleukin-2 (IL-2), thereby dampening CD8 T cell-mediated antitumor responses. We generated novel acid-resistant immunocytokines that blocked CD47 and PD-L1 activities and simultaneously activated IL-2 signaling in tumor- infiltrating CD8 T cells, leading to markedly enhanced antitumor efficacy and reduced systemic toxicity in the mouse model of OS. To target tumor cell-intrinsic mechanisms underlying immune evasion, we performed in vitro CRISPR epigenetic screening and identified evolutionarily conserved epigenetic modifiers involved in negative modulating tumor antigen presentation machinery. Here, we hypothesize that targeting these epigenetic modifiers in conjunction with acid-resistant immunocytokines will significantly enhance tumor antigen presentation, leading to more robust systemic antitumor responses for tumor eradication. In this study, we will investigate the function of these pMHC-I epigenetic regulators and assess the antitumor synergy of acid-resistant immunocytokine therapy with the inactivation of these epigenetic modifiers in clinically relevant mouse models of OS. Project Number: 1R21CA299552-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Tao Yue | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $426,828 | Activity Code: R21 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11302950