Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non-small cell lung cancer.
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ICR Authors
Authors
Wennerberg, E
Mukherjee, S
Spada, S
Hung, C
Agrusa, CJ
Chen, C
Valeta-Magara, A
Rudqvist, N-P
Van Nest, SJ
Kamel, MK
Nasar, A
Narula, N
Mittal, V
Markowitz, GJ
Zhou, XK
Adusumilli, PS
Borczuk, AC
White, TE
Khan, AG
Balderes, PJ
Lorenz, IC
Altorki, N
Demaria, S
McGraw, TE
Stiles, BM
Mukherjee, S
Spada, S
Hung, C
Agrusa, CJ
Chen, C
Valeta-Magara, A
Rudqvist, N-P
Van Nest, SJ
Kamel, MK
Nasar, A
Narula, N
Mittal, V
Markowitz, GJ
Zhou, XK
Adusumilli, PS
Borczuk, AC
White, TE
Khan, AG
Balderes, PJ
Lorenz, IC
Altorki, N
Demaria, S
McGraw, TE
Stiles, BM
Document Type
Journal Article
Date
2022-03-16
Date Accepted
2022-02-22
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.
Citation
Science Translational Medicine, 2022, 14 (636), pp. eabe8195 -
Source Title
Science Translational Medicine
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
ISSN
1946-6234
eISSN
1946-6242
1946-6242
1946-6242
Collections
Research Team
Radiation Immunotherapy