MLL4/KMT2D mutations increase immune activity and predict therapyefficacy in colorectal cancer

Abstract

BackgroundThe KMT2D histone 3-lysine 4 methyltransferase (also known as MLL4) is a critical chromatin regulator, which is frequently inactivated by gene mutations in various types of cancer including colorectal cancer (CRC). Several lines of evidence suggest a strong association between chromatin regulation, tumor immunity and drug sensitivity. To explore the role of KMT2D in tumor immunity, we analyzed genomic and clinical datasets from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center for various cancer entities. ResultThe results showed that KMT2D-mutated CRCs displayed a significantly higher expression of immune checkpoint regulators including PD-L1, CTLA4 and CD8 when compared to KMT2D wild-type CRCs. Mutations in KMT2D correlate with elevated T-effector and interferon-{gamma} gene signatures indicating infiltration with active immune cells. By performing immune cell deconvolution from transcriptomic data, CRCs harboring KMT2D mutations are associated with increased infiltration of CD8+ T cells, NK cells and macrophages, but they display low amounts of Treg cells suggesting that KMT2D loss-of-function mutations correlate with an immunologically "hot tumor" phenotype. Furthermore, patients with KMT2D mutant CRC displayed better clinical responses to immune checkpoint inhibitor (ICI) therapy with an improved overall patient survival compared to patients with KMT2D wild-type CRC. Importantly, this effect did not exist in cohorts of CRC patients, which have not been treated with immunotherapies. To further understand the differential drug response effect related to KMT2D, we treated wild-type and KMT2D inactive epithelial cells with various cancer drugs. KMT2D mutant cells exhibited increased DNA damage and higher sensitivity to cisplatin in comparison to KMT2D wild-type cells. ConclusionsKMT2D loss-of-function mutations are associated with a positive outcome of immunotherapy efficacy in CRC and responses to cisplatin treatments. The stratification of CRC patients by KMT2D gene status may enable personalized approaches by identifying CRC patient populations that benefit from ICI therapy and chemotherapy.