Effects of Combinatorial Ubiquitinated Protein-Based Nanovaccine and STING Agonist in Mice With Drug-Resistant and Metastatic Breast Cancer

Abstract

We previously reported that enriched ubiquitinated proteins (UPs) from tumor cells have the potential to be used as immunotherapy vaccine against cancer. Here we enriched UPs from epirubicin (EPB)-induced multi-drug-resistant cancer stem-like breast cancer cell line (4T1/EPB) and tested the efficacy of α-Al2O3-UPs-4T1/EPB (short for UPs-4T1/EPB) as therapeutic vaccine alone and in combination with the stimulator of interferon genes (STING) agonist in mice with drug-resistant and metastatic breast cancer. Vaccination with UPs-4T1/EPB exerted profound anti-tumor effects through augmented specific CD8+ T cell responses and amplified T cell receptor diversity of tumor-infiltrating lymphocytes (TILs). Importantly, the combination with STING agonist further facilitated the migration of mature CD8α+ dendritic cells to the lymph nodes and the infiltration of TILs within tumors, resulting in primary tumor regression and pulmonary metastasis eradication in mice. Moreover, the cured mice were completely resistant against a subsequent rechallenge with the same tumor. Our study indicates that this novel combinatorial immunotherapy with UPs-4T1/EPB vaccine and STING agonist is effective in mice with drug-resistant and metastatic breast cancer.

Updates in combined approaches of radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer

“…For instance, combining a phosphoinositide 3-kinase δ (PI3Kαδ) inhibitor with radiotherapy and anti-PD-1 was found to increase CD8 + T cell accumulation and delay tumor growth in a murine syngeneic TNBC model ( 264 ). STING agonists are also currently being examined in preclinical breast cancer models in combination with ubiquitinated protein nanovaccines ( 265 ), anti-CD47 monoclonal antibodies ( 266 ), and CAR-T cell therapy ( 267 ). These studies suggest that combining STING agonists, ICIs, and radiotherapy may have clinical potential.…”