Common inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy.

Barnet, MB; Jackson, KJL; Masle-Farquhar, E; Russell, A; Burnett, DL; Chye, A; Jara, CJ; Faulks, M; Mawson, A; Peters, TJ; Brink, R; Wright, K; Allen, I; Junankar, S; Davis, ID; Heller, G; Khan, Z; Bruce, J; Yang, C; Prokopec, S; Pugh, T; Behren, A; Hold, GL; Zhang, F; Cooper, WA; Gao, B; Nagrial, A; Joshua, AM; John, T; Peters, G; Hui, R; Boyer, M; Blinman, PL; Kao, SC; Cebon, J; Goodnow, CC

Common inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy.

Barnet, MB Jackson, KJL Masle-Farquhar, E Russell, A Burnett, DL Chye, A Jara, CJ Faulks, M Mawson, A Peters, TJ Brink, R Wright, K Allen, I Junankar, S Davis, ID Heller, G Khan, Z Bruce, J Yang, C Prokopec, S Pugh, T Behren, A Hold, GL Zhang, F Cooper, WA Gao, B Nagrial, A Joshua, AM John, T Peters, G Hui, R Boyer, M Blinman, PL Kao, SC Cebon, J Goodnow, CC

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Publisher:: Proceedings of the National Academy of Sciences
Publication Type:: Journal Article
Citation:: Proc Natl Acad Sci U S A, 2025, 122, (28), pp. e2314258122
Issue Date:: 2025-07-15

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Field	Value	Language
dc.contributor.author	Barnet, MB
dc.contributor.author	Jackson, KJL
dc.contributor.author	Masle-Farquhar, E
dc.contributor.author	Russell, A
dc.contributor.author	Burnett, DL
dc.contributor.author	Chye, A
dc.contributor.author	Jara, CJ
dc.contributor.author	Faulks, M
dc.contributor.author	Mawson, A
dc.contributor.author	Peters, TJ
dc.contributor.author	Brink, R
dc.contributor.author	Wright, K
dc.contributor.author	Allen, I
dc.contributor.author	Junankar, S
dc.contributor.author	Davis, ID
dc.contributor.author	Heller, G
dc.contributor.author	Khan, Z
dc.contributor.author	Bruce, J
dc.contributor.author	Yang, C
dc.contributor.author	Prokopec, S
dc.contributor.author	Pugh, T
dc.contributor.author	Behren, A
dc.contributor.author	Hold, GL
dc.contributor.author	Zhang, F
dc.contributor.author	Cooper, WA
dc.contributor.author	Gao, B
dc.contributor.author	Nagrial, A
dc.contributor.author	Joshua, AM
dc.contributor.author	John, T
dc.contributor.author	Peters, G
dc.contributor.author	Hui, R
dc.contributor.author	Boyer, M
dc.contributor.author	Blinman, PL
dc.contributor.author	Kao, SC
dc.contributor.author	Cebon, J
dc.contributor.author	Goodnow, CC
dc.date.accessioned	2026-01-12T04:16:01Z
dc.date.available	2026-01-12T04:16:01Z
dc.date.issued	2025-07-15
dc.identifier.citation	Proc Natl Acad Sci U S A, 2025, 122, (28), pp. e2314258122
dc.identifier.issn	0027-8424
dc.identifier.issn	1091-6490
dc.identifier.uri	http://hdl.handle.net/10453/191650
dc.description.abstract	Lung cancers and melanomas have many somatically mutated self-proteins that would be expected to trigger an immune rejection response, yet therapeutic responses can only be induced in a subset of patients. Here, we investigated the possibility that inherited differences in immune tolerance checkpoints contribute to variability in outcomes. Whole genome sequencing revealed biallelic germline loss-of-function (LOF) mutations in the immune tolerance checkpoint gene, NOD2, in an exceptional immune responder to targeted radiotherapy for metastatic melanoma. In 40 exceptional immune responders to anti-PD1 monotherapy for non-small cell lung cancer (NSCLC), genome sequencing showed 30% had inherited a NOD2 LOF variant, more than twice the population frequency (P = 0.0021). Conversely, a gain-of-function RIPK2 allele known to increase NOD2 signaling was inherited by 61% of nonresponders from the same cohort, compared to 10% of exceptional responders and much higher than the population frequency (P < 0.0001). Within the overall recruited cohort of 144 NSCLC anti-PD1 patients, individuals with immune-related adverse events (irAE) had better overall survival, further improved in those with NOD2 LOF. In independent anti-PD1 monotherapy cohorts with a range of cancers, inherited NOD2 LOF was associated with complete or partial response (P = 0.0107). Experimental validation in mice showed germline Nod2 LOF enhanced therapeutic immune responses elicited by anti-PD1 monotherapy against a high mutation burden colorectal cancer, increasing tumor infiltration by effector memory CD8 T cells. Collectively these results reveal common inherited human variation in an immune tolerance checkpoint is a determinant of cancer immune responses elicited by pharmacological inhibition of another checkpoint.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Proceedings of the National Academy of Sciences
dc.relation.ispartof	Proc Natl Acad Sci U S A
dc.relation.isbasedon	10.1073/pnas.2314258122
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Nod2 Signaling Adaptor Protein
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Immunotherapy
dc.subject.mesh	Mice
dc.subject.mesh	Loss of Function Mutation
dc.subject.mesh	Carcinoma, Non-Small-Cell Lung
dc.subject.mesh	Female
dc.subject.mesh	Lung Neoplasms
dc.subject.mesh	Male
dc.subject.mesh	Melanoma
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Programmed Cell Death 1 Receptor
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Melanoma
dc.subject.mesh	Carcinoma, Non-Small-Cell Lung
dc.subject.mesh	Lung Neoplasms
dc.subject.mesh	Immunotherapy
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Nod2 Signaling Adaptor Protein
dc.subject.mesh	Programmed Cell Death 1 Receptor
dc.subject.mesh	Loss of Function Mutation
dc.subject.mesh	Nod2 Signaling Adaptor Protein
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Immunotherapy
dc.subject.mesh	Mice
dc.subject.mesh	Loss of Function Mutation
dc.subject.mesh	Carcinoma, Non-Small-Cell Lung
dc.subject.mesh	Female
dc.subject.mesh	Lung Neoplasms
dc.subject.mesh	Male
dc.subject.mesh	Melanoma
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Programmed Cell Death 1 Receptor
dc.title	Common inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy.
dc.type	Journal Article
utslib.citation.volume	122
utslib.location.activity	United States
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/INSIGHT: Institute for Innovative Solutions for Wellbeing and Health
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2026-01-12T04:15:56Z
pubs.issue	28
pubs.publication-status	Published
pubs.volume	122
utslib.citation.issue	28

Abstract:

Lung cancers and melanomas have many somatically mutated self-proteins that would be expected to trigger an immune rejection response, yet therapeutic responses can only be induced in a subset of patients. Here, we investigated the possibility that inherited differences in immune tolerance checkpoints contribute to variability in outcomes. Whole genome sequencing revealed biallelic germline loss-of-function (LOF) mutations in the immune tolerance checkpoint gene, NOD2, in an exceptional immune responder to targeted radiotherapy for metastatic melanoma. In 40 exceptional immune responders to anti-PD1 monotherapy for non-small cell lung cancer (NSCLC), genome sequencing showed 30% had inherited a NOD2 LOF variant, more than twice the population frequency (P = 0.0021). Conversely, a gain-of-function RIPK2 allele known to increase NOD2 signaling was inherited by 61% of nonresponders from the same cohort, compared to 10% of exceptional responders and much higher than the population frequency (P < 0.0001). Within the overall recruited cohort of 144 NSCLC anti-PD1 patients, individuals with immune-related adverse events (irAE) had better overall survival, further improved in those with NOD2 LOF. In independent anti-PD1 monotherapy cohorts with a range of cancers, inherited NOD2 LOF was associated with complete or partial response (P = 0.0107). Experimental validation in mice showed germline Nod2 LOF enhanced therapeutic immune responses elicited by anti-PD1 monotherapy against a high mutation burden colorectal cancer, increasing tumor infiltration by effector memory CD8 T cells. Collectively these results reveal common inherited human variation in an immune tolerance checkpoint is a determinant of cancer immune responses elicited by pharmacological inhibition of another checkpoint.

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http://hdl.handle.net/10453/191650