Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non–small cell lung cancer

Abstract

Most patients with non–small cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. Nicotinamide adenine dinucleotide (NAD)–induced cell death (NICD) of P2X7 receptor (P2X7R)–expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono–adenosine 5′-diphosphate (ADP)–ribosyltransferases (ARTs). We found an association between membranous expression of ART1 on tumor cells and reduced CD8 T cell infiltration. Specifically, we observed a reduction in the P2X7R + CD8 T cell subset in human lung adenocarcinomas. In vitro, P2X7R + CD8 T cells were susceptible to ART1-mediated ADP-ribosylation and NICD, which was exacerbated upon blockade of the NAD + -degrading ADP-ribosyl cyclase CD38. Last, in murine NSCLC and melanoma models, we demonstrate that genetic and antibody-mediated ART1 inhibition slowed tumor growth in a CD8 T cell–dependent manner. This was associated with increased infiltration of activated P2X7R + CD8 T cells into tumors. In conclusion, we describe ART1-mediated NICD as a mechanism of immune resistance in NSCLC and provide preclinical evidence that antibody-mediated targeting of ART1 can improve tumor control, supporting pursuit of this approach in clinical studies.

Targeted Nanophotoimmunotherapy Potentiates Cancer Treatment by Enhancing Tumor Immunogenicity and Improving the Immunosuppressive Tumor Microenvironment

“…B7 family related protein V-set and Ig domain-containing 4 (VSIG4) and B7–H3 (CD276) are negative regulators of T cell activation. Some new targets are associated with tumor immune escape: DDR1 (discoidin domain receptor 1), mono-ADP-ribosyltransferase 1 (ART1), endosomal sorting complex required for transport (ESCRT) proteins, and CD161 . Several newly discovered targets have been shown to affect macrophage function: P-selectin glycoprotein ligand-1 (PSGL-1), E3 ubiquitin ligase Cop1, and G protein-coupled receptor 65 (GPR65) .…”

Multi-Omics Approaches for the Prediction of Clinical Endpoints after Immunotherapy in Non-Small Cell Lung Cancer: A Comprehensive Review

“…Specific genes such as KLRG1, BTK, CCR2 and SCML4 were associated with poor responses to immunotherapy [ 67 ]. ART1 expression, for example, drives ICI resistance by promoting CD8 + T-cell death and could be a therapeutic target [ 68 ]. Other genes (JAK1/JAK2) also appear as potential targets to restore the efficacy of ICIs [ 69 ].…”

Emerging insights to lung cancer drug resistance

“…LKB1mutation also results in the recruitment of suppressive myeloid cells, and the inhibition of granulocytic myeloid-derived suppressor cells (G-MDSCs) via all-trans-retinoic acid could overcome the resistance of PD-1 blockade in LKB1-deficient murine NSCLC [28] . Yang et al discovered that USP12 downregulation fostered an immunosuppressive microenvironment with increased macrophage recruitment and reduced Tcell activation via NF-κB hyperactivation in tumor cells [29] . Recently, Wennerberg et al described the expression of mono-adenosine 5'-diphosphate-ribosyltransferase 1 (ART1) on tumor cell-mediated cell death of P2X7R+ CD8 T cells as a novel mechanism of immune resistance in NSCLC and provided preclinical evidence that antibody-mediated targeting of ART1 could improve tumor control [30] .…”

“…Recently, Wennerberg et al . described the expression of mono-adenosine 5’-diphosphate-ribosyltransferase 1 (ART1) on tumor cell-mediated cell death of P2X7R+ CD8 T cells as a novel mechanism of immune resistance in NSCLC and provided preclinical evidence that antibody-mediated targeting of ART1 could improve tumor control [ 30 ] . Tumor-extrinsic factors are those components beyond cancer cells that contribute to suppressive TME.…”