CHARACTERIZATION AND TARGETING OF DNA DAMAGE-LINKED SURFACE MARKERS ON TUMOUR CELLS

Abstract

Tumorigenesis is characterized by genomic instability and engagement of DNA repair pathways. Activation of the DNA damage response induces downstream signaling to alert the immune system to a potential threat. Understanding immunoregulatory mechanisms governing immune-mediated elimination of tumor cells can be exploited for the treatment of cancer. We show that DNA damage-mediated activation of tumoral STING contributes to anti-cancer immunity. STING-deficiency resulted in impaired immune activation in the tumor microenvironment. STING was also required for DNA damage-induced upregulation of cell surface ICAM-1. We found that LY6K, too, was also upregulated following DNA damage. LY6K represents an attractive target for antibody-based immunotherapy. We developed high affinity antibodies targeting LY6K on the surface of various cancer cell lines. We showed that antibodies induced tumor killing in cervical cancer and one of the antibodies discriminated cancerous from healthy tissues from tongue and lung cancer patients, thus providing evidence for the potential use for LY6K-targeting antibodies in cancer treatment and diagnosis.