Use of a cytotoxic peptide as an immunotherapeutic agent in the treatment of metastatic breast cancer (VAC13P.1134)

Abstract

Abstract Breast cancer is a challenge for immunotherapy because of its genetic heterogeneity and decreased immunogenicity, which impedes the use of immune checkpoint blockade. A promising approach is to generate dying cancer cells that operate like a vaccine to induce a tumor-specific immune response and eradicate residual cancer cells. This is termed immunogenic cell death (ICD) and is characterized by a unique molecular signature that stimulates immunity. To develop a novel ICD agent for cancer immunotherapy, our group discovered a therapeutic peptide, CT20p, and a nanotechnology-based platform to concentrate CT20p in breast tumors. Treatment of mice with nanomolar amounts of CT20p caused tumor regression, and dying breast cancer cells expressed markers characteristic of ICD: calreticulin (Crt) and heat shock protein (HSP)-70. The intracellular target of CT20p is a protein called chaperonin-containing T-complex (CCT) that folds actin and tubulin. CCT was overexpressed in breast cancer cells susceptible to CT20p. In contrast, normal epithelial cells, macrophages or NK cells, which have low levels of CCT, were unaffected by CT20p. Breast cancer cells treated with CT20p displayed alterations in IRE1 and PERK, mediators of the unfolded protein response (UPR) that are upstream drivers of ICD signals. Hence, CT20p-treated breast cancer cells were more effectively killed by NK cells and ingested by phagocytes, demonstrating that CT20p is a robust stimulator of innate immunity.