PO-399 Tumour CDKN2A loss predisposes to immunotherapy resistance

Abstract

IntroductionIn recent years, treatment with immunomodulating antibodies targeting the inhibitory T-cell receptor PD-1 led to durable clinical responses in a subgroup of patients with melanoma, lung cancer or bladder cancer. Nevertheless, the majority of the patients do not respond, and the mechanisms underlying primary or acquired resistance are still poorly defined. Recently, it was demonstrated that mutations in the JAK1/2-STAT1 signalling pathway play an essential role in protecting tumour cells from the anti-proliferative and pro-apoptotic activity of T cell-derived IFNg thereby contributing to immunotherapy resistance.Material and methodsJAK2 mutational status in melanoma cells was defined by targeted sequencing. JAK2 and p16 expression was studied by immunoblotting. Single nucleotide polymorphism array data of 46 melanoma cell lines was screened for deletions on Chr.9p to which JAK2 and CDKN2A (encoding p16) map. cBioPortal for Cancer Genomics was applied to analyse melanoma, lung squamous cell carcinoma and bladder urothelial carcinoma data sets of The Cancer Genome Atlas (TCGA) for association of CDKN2A and JAK2 deletions. The UCSC Xena Browser was used to visualise alterations in Chr.9p segments of TCGA tissue samples.Results and discussionsIn this study we demonstrate the genetic evolution of JAK2 deficiency in melanoma cells. JAK2-deficient melanoma cells showed an inactivating mutation in one JAK2 allele and loss of the second allele. SNP array analyses revealed large deletions on chr9p in these cells, in the region where JAK2 maps together with CDKN2A, the latter encoding the tumour suppressor p16. Loss of CDKN2A is known as an early frequent event in melanoma development. Accordingly, in a cohort of 46 melanoma cell lines, we detected CDKN2A-associated JAK2 deletions in more than 75%. Co-deletion of JAK2 and CDKN2A was detected also in TCGA melanoma tissues and, interestingly, in a large fraction of samples from different tumour types, including lung squamous cell carcinoma and bladder urothelial carcinoma.ConclusionThis result demonstrates that tumours harbouring allelic CDKN2A deletions may be more prone to develop resistance to immunotherapy due to associated JAK2 allele losses.