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- Title
Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non–small cell lung cancer.
- Authors
Wennerberg, Erik; Mukherjee, Sumit; Spada, Sheila; Hung, Clarey; Agrusa, Christopher J.; Chen, Chuang; Valeta-Magara, Amanda; Rudqvist, Nils-Petter; Van Nest, Samantha J.; Kamel, Mohamed K.; Nasar, Abu; Narula, Navneet; Mittal, Vivek; Markowitz, Geoffrey J.; Zhou, Xi Kathy; Adusumilli, Prasad S.; Borczuk, Alain C.; White, Thomas E.; Khan, Abdul G.; Balderes, Paul J.
- 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. An ARTistic approach: Immune checkpoint inhibitors have revolutionized cancer immunotherapy, but some patients with non–small cell lung cancer (NSCLC) do not respond. Here, Wennerberg et al. investigated whether additional mechanisms of immune suppression may drive lack of responses in these patients. The authors found that membranous expression of the mono-ADP-ribosyltransferase 1 (ART1) was associated with poorer CD8 T cell infiltration in tumor samples from patients. Using mouse models, the authors showed that ART1 mediated immune resistance by driving NAD-induced cell death of CD8 T cells, which could be reversed with an antibody targeting ART1. Together, these findings identify ART1 as a targetable mediator of immune resistance in NSCLC.
- Subjects
NON-small-cell lung carcinoma; CELL death; IMMUNE checkpoint inhibitors; T cells; PROGRAMMED cell death 1 receptors
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 636, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abe8195