NLRC5 germline variants as potential pharmacogenomic markers for immune checkpoint inhibitors

• Published in: Journal for immunotherapy of cancer 2023-06, Vol.11 (6), p.e007255
• Main Author: Meng, Xiang-Yu
• Format: Article
• Language: English
• Subjects: Antigen presentation; Biomarkers; biomarkers, tumor; Biomarkers, Tumor - genetics; Bladder cancer; Cancer; Diabetes; Gene expression; genetic markers; Germ Cells; Germ-Line Mutation; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Intracellular Signaling Peptides and Proteins; Letter; Melanoma; Pharmacogenetics; Roles; Tumors
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-007255

[...]as also discussed in Caulfield et al, the NLRC5 gene has been experimentally shown to play an important role in the development of IFNα-induced autoimmunity against pancreatic β cells, through not only transcriptional activation of HLA class I and antigen presentation-related genes, but also generation of β cell neoantigens by cross-talk with alternative splicing.1 Second, although the NLRC5 Pro191Leu amino acid change may confer non-significant impact on the function of NLRC5 protein, this variant is indeed significantly associated with the NLRC5 gene expression level in blood, as shown in the eQTLGen database (https://eqtlgen.org; rs74439742 T vs C, n=13 100, Z-score=−5.1, p=2.8×10−7, FDR=8.6×10−4). [...]no NLRC5 genetic variants have been linked with type I diabetes (T1DM) at genome-wide significance in GWAS studies so far, per queries in the GWAS Catalog (https://www.ebi.ac.uk/gwas) and IEU-GWAS (https://gwas.mrcieu.ac.uk) databases, which is consistent with the report by Caulfield et al that no significant difference in the allele-frequency of NLRC5 Pro191Leu was noted between the T1DM subjects and the controls in previously published T1DM datasets and the Type 1 Diabetes Genetics Consortium database.1 However, interestingly, summary statistics-based Mendelian randomization (SMR) analyses suggest a possible cause-and-effect relationship between NLRC5 and T1DM, as provided in the eQTLGen database (βSMR=−0.40, PSMR=3.3×10−2). Considering the contributing effects exerted by genetic variants in anticancer immunity and ICI-response, NLRC5 variants could be potential biomarkers for ICI responsiveness and efficacy, similar as the previously identified marker SNPs associated with CTLA4, PDCD1, and CD274 genes.3 4 On the other hand, per query in the GTEx database (https://www.gtexportal.org/), although immune-related tissue types present the highest expression level of NLRC5 (ie, spleen and whole blood, median TPM, 63.98 and 35.93, respectively), it is also widely expressed in many other tissue types, and at a high level in lung, small intestine, and skin (median TPM, 24.63, 22.05, and 19.15, respectively). [...]if NLRC5 does play a role in irAE and with possible effects conferred by its germline variants, presumably ICI-DM is not the only form of manifestation.