Targeting ART1, a Novel Immune Checkpoint, for the Treatment of Lung Cancer

ABSTRACT

We have found ART1 expressed in multiple human non-small cell lung cancer (NSCLC) cell lines and in mouse and human NSCLC tumors. ART1, an ARTC family mono-ADP-ribosyltransferase, functions extracellularly to target arginine-rich cell surface proteins on neighboring cells or target soluble proteins in the local tumor microenvironment. Following ART1 knockdown in murine immune competent lung cancer models, we note a highly significant increase in cytotoxic tumor infiltrating CD8 T cells and a subsequent decrease in tumor burden. Mono-ADP-ribosylation of the P2X7 receptor on subsets of CD8 T cells may induce receptor activation and apoptosis, a process described as NAD-induced cell death (NICD). ART1-induced mono-ADP-ribosylation of P2X7R could therefore allow cancer cells overexpressing ART1 to blunt the T cell immune response against them by inducing T cell apoptosis. Although little is known about ART1 in human cancer, its expression may be upregulated by ER stress and its enzymatic activity increased by release of NAD into the local microenvironment, both of which occur following cytotoxic cancer therapy, particularly radiation therapy. In the current application addressing the LCRP Area of Emphasis Identify innovative strategies for prevention and treatment of lung cancer, we therefore propose to evaluate the therapeutic efficacy of anti-ART1 antibodies which we have already developed and functionally optimized and to determine whether ART1 blockade has additive anti-tumor effects to immune checkpoint blockade and radiation therapy. We hypothesize that therapeutic inhibition of ART1 with an anti-ART1 monoclonal antibody will promote immune mediated rejection of lung cancer. Moreover, we hypothesize that ART1 inhibition combined with radiation therapy will demonstrate synergistic anti-tumor effects.