Engineered Synthetic Low-Density Lipoprotein Nanoparticles for Enhanced Cancer Immunotherapy in Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Despite technological advancements, the 5-year survival rate for advanced HNSCC has remained stagnant for the past three decades. The FDA has approved immune checkpoint inhibitors (ICIs), including pembrolizumab and nivolumab, for the treatment of recurrent and metastatic HNSCC. While immunotherapy can induce durable remissions, only 15–20% of patients respond to treatment. There is growing interest in combining ICIs with chemotherapy or radiotherapy to enhance therapeutic efficacy. However, this approach has faced significant setbacks in recent clinical trials. Emerging studies suggest that the lack of activated dendritic cells (DCs) in tumors is a major reason for immunotherapy failure. Therefore, developing therapeutic strategies that not only eliminate cancer cells but also release stimulatory factors to promote intratumoral DC maturation and migration holds great promise for enhancing tumor sensitivity to immunotherapy. Our goal is to develop a novel adjuvant nanotechnology based on 7-dehydrocholesterol (7DHC)- encapsulated synthetic low-density lipoproteins (7DHC-LDLs) to boost anti-tumor immunity when used in combination with ICIs. 7DHC, a cholesterol analog, exhibits the highest rate of free radical chain propagation among known lipid molecules. Our preliminary data demonstrate that 7DHC-LDLs, like natural LDLs, accumulate in tumors by binding to the LDL receptor, which is upregulated in HNSCC. In the presence of reactive oxygen species (ROS), 7DHC triggers and amplifies lipid peroxidation in cell membranes, leading to ferroptotic cell death. In addition, our data suggest that cancer cells killed by 7DHC release danger-associated molecular patterns (DAMPs) and pro-inflammatory cytokines, which activate DCs and enhance tumor-reactive T cell priming, even in immunologically “cold” tumors. In this project, we will evaluate the pharmacokinetics and biodistribution of 7DHC-LDLs in orthotopic HNSCC models. We will test whether the innate adjuvant effects of 7DHC-LDLs can be leveraged to enhance the efficacy of anti-PD-L1 checkpoint blockade. Finally, we will perform a comprehensive analysis of the tumor microenvironment to elucidate the impact of this combination therapy.

Funder: NIH

Amount: $3,072,426

PI: Jin Xie, Franklin College of Arts and Sciences, Department of Chemistry