Response to "NLRC5 germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng

• Published in: Journal for immunotherapy of cancer Vol. 11; no. 6; p. e007397
• Main Authors: Aizenbud, Lilach, Schoenfeld, David A, Caulfield, Jasmine I, Mann, Jacqueline E, Austin, Matthew R, Perdigoto, Ana Luisa, Herold, Kevan C, Kluger, Harriet M
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.06.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Antigens; Biomarkers; Cancer; Diabetes; genetic markers; Germ Cells; Germ-Line Mutation; Humans; Immune Checkpoint Inhibitors; Immunity; Immunotherapy; Intracellular Signaling Peptides and Proteins; Letter; Mutation; Neoplasms - drug therapy; Skin cancer; genetic markers; immune checkpoint inhibitors
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-007397

Dr Meng further highlights a potential role of NLRC5 expression or polymorphisms as a biomarker for predicting response to immunotherapy, based on work by Yoshihama et al.1 Despite several protein structure tools predicting a benign effect of the NLRC5 variant identified (Pro191Leu), as detailed in our study2 and by Dr Meng, we agree that the mutant gene may still play a causal role in ICI-DM. Regarding the potential of NLRC5 as a predictive biomarker of tumor response to ICIs, there are emerging reports connecting NLRC5 to treatment response for various cancers,3 4 with multiple studies suggesting that the mechanism is based on tumor evasion and mediated by human leukocyte antigens (HLA) expression.5 Additionally, the correlation between irAEs and favorable response to ICIs has been widely demonstrated, and Jiang et al recently suggested that HLA alterations are the link between the two.6 While our initial cohort size of 13 patients limited our ability to connect the NLRC5 germline variant with response to ICIs, we are performing this analysis in the larger cohort of ICI-treated patients we are currently investigating. [...]we appreciate the additional analysis and comments provided by Dr Meng related to our study, and believe they support further efforts to better understand the role of NLRC5 in irAEs and response to ICIs, some of which are underway in our group.