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

• 成果类型: Article
• 署名作者: Barnet, Megan B.; L., Katherine J.; Masle, Etienne; Russell, Amanda; Burnett, Deborah L.; Chye, Adrian; Jara, Chris J.; Faulks, Megan; Mawson, Amanda; Peters, Timothy J.; Brink, Robert; Wright, Katherine; Allen, India; Junankar, Simon; Davis, Ian D.; Heller, Gillian; Khan, Zia; Bruce, Jeffrey; Yang, Cindy; Prokopec, Stephenie; Pugh, Trevor; Behren, Andreas; Hold, Georgina L.; Zhang, Fan; Cooper, Wendy A.; Gao, Bo; Nagrial, Adnan; Joshua, Anthony M.; John, Thomas; Peters, Geoffrey; Hui, Rina; Boyer, Michael; Blinman, Prunella L.; Kao, Steven C.; Cebon, Jonathan; Goodnow, Christopher C.
• 署名单位: Garvan Institute of Medical Research; University of New South Wales Sydney; NSW Health; St Vincents Hospital Sydney; The Kinghorn Cancer Centre; University of Technology Sydney; University of New South Wales Sydney; University of New South Wales Sydney; Monash University; La Trobe University; Olivia Newton-John Cancer Research Institute; Eastern Health; University of Sydney; Roche Holding; Genentech; Roche Holding USA; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; La Trobe University; University of Melbourne; University of New South Wales Sydney; Western Sydney University; University of Sydney; NSW Health; Royal Prince Alfred Hospital; University of Sydney; NSW Health; Blacktown & Mount Druitt Hospital; University of Sydney; NSW Health; Westmead Hospital; Peter Maccallum Cancer Center; Chris O'Brien Lifehouse; Concord Repatriation General Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13551
• DOI: 10.1073/pnas.2314258122
• 发表日期: 2025-07-15
• 关键词: crohns-disease; open-label; checkpoint blockade; muramyl dipeptide; adverse events; metastatic melanoma; cell; association; variants; multicenter

摘要

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.