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

Author(s): 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;
Details: Publication Year 2025-07-15,Volume 122,Issue #28,Page e2314258122
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Publication Type: Research article
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.
Publisher: National Academy of Sciences
Keywords: *Nod2 Signaling Adaptor Protein/genetics/immunology; Humans; Animals; *Immunotherapy/methods; Mice; *Loss of Function Mutation; *Carcinoma, Non-Small-Cell Lung/genetics/immunology/therapy; Female; *Lung Neoplasms/genetics/immunology/therapy; Male; Melanoma/genetics/immunology/therapy; Germ-Line Mutation; Programmed Cell Death 1 Receptor/antagonists & inhibitors; autoimmune disease; cancer immunotherapy; immune checkpoint inhibitor; immune-related adverse event; inherited variant
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1073/pnas.2314258122
Open Access at Publisher's Site: https://doi.org/10.1073/pnas.231425812210.1073/pnas.2314258122
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-07-22 03:30:51

Last Modified: 2025-07-22 03:31:16