Targeting ZC3H11A elicits immunogenic cancer cell death through augmentation of antigen presentation and interferon response

Zinc finger CCCH containing 11A (ZC3H11A) is a stress-induced protein that is upregulated in various conditions such as heat shock and virus infection. It has also been reported to be upregulated in certain cancers. The aim of this study was to evaluate the feasibility of targeting ZC3H11A as a therapeutic approach for cancer treatment, using nuclease-resistant, affinity-enhanced antisense oligonucleotide (ASO). An ASO targeting ZC3H11A was validated and evaluated in vitro and in the B16 melanoma model in vivo. Antigen presentation, interferon response, cell proliferation, and apoptosis were transcriptionally affected. These findings were validated on the protein level by the upregulation of major histocompatibility complex class I (MHC class I), an increased secretion of interferon-β (IFN-β), and induction of apoptosis observed as upregulation of caspases and annexin V. Immunogenic features of the induced apoptosis were evidenced by the surface exposure of calreticulin (CRT) and the secretion of ATP leading to enhanced dendritic cell (DC) phagocytosis, maturation, and activation. Treatment with the ZC3H11A-targeted ASO had limited efficacy in vivo, while constitutive lentiviral shRNA knockdown of ZC3H11A in murine B16 melanoma cells and human HeLa cells led to reduced tumor growth with prolonged survival of mice, validating ZC3H11A as a relevant target for cancer therapy.