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.
Highlights
Breast cancer is the most common malignancy and the second cause of cancer-related deaths in women worldwide [1]
The in vivo experiments showed that the s.c. inoculation of 4T1/EPB cells significantly reduced the chemosensitivity to EPB compared to the 4T1/WT inoculation (Figures 1B, C and Supplementary Figure S1A)
It is important to note that the dendritic cells (DCs) treated with Dimethylxanthenone-4-acetic acid (DMXAA) can cause IFN-g responses from splenocytes without an antigen present. This result is in line with previous report in that DMXAA could induce IFN-g production in unstimulated T cells [37, 38]. These results suggest that DMXAA, on top of ubiquitinated proteins (UPs)-4T1/EPB nanovaccine, results in more significant activation, maturation, and migration of the UPs-4T1/ EPB-loaded DCs to draining lymph nodes (DLNs) through stimulating the secretion of IFN-b and IL-12, enhancing CD8+ T cell responses, and enhancing CD8+ tumor-infiltrating lymphocytes (TILs) infiltration in the tumor tissue, leading to complete tumor eradication in this model
Summary
Breast cancer is the most common malignancy and the second cause of cancer-related deaths in women worldwide [1]. The therapeutic efficacy is often limited by multi-drug resistance (MDR) in that tumor cells develop resistance to one or more chemotherapy drugs, clinically presenting as a failure of chemotherapy, tumor metastasis, or tumor recurrence [3]. Continuous efforts are made to develop novel therapeutic strategies for drug-resistant and metastatic breast cancer. One of the most attractive immunotherapeutic strategies is therapeutic cancer vaccination, which is capable of eliminating the primary and metastatic tumor lesions through inducing the generation of UPs-Nanovaccine Combined With STING Agonist antigen-specific cytotoxic T lymphocytes (CTLs) and specific immunological memory. Cancer vaccines have not yet achieved the expected clinical benefit in breast cancer patients mainly due to the failure to obtain sufficient tumor-associated antigens (TAAs) and initiate an efficient antigen presentation of TAAs [5, 6]
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