Abstract 1639: Correlation of KMT2C/D loss-of-function mutations with PD-L1 expression and response to immune checkpoint inhibitors in solid tumors
Authors: Liang Naixin , Niu Yanling , Ma Tonghui , Zhang Xin 
Published: July 2021

Background: Dysregulation of histone lysine methyltransferases plays important roles in the development of cancer. KMT2C and KMT2D are enzymatically active proteins that form the core of mammalian COMPASS complexes, which methylate the histone 3 lysine 4 (H3K4). A previous study revealed that PD-L1 expression is tightly controlled by H3K4 trimethylation. PD-L1 expression is a predictive biomarker for the efficacy of immune checkpoint inhibitors (ICIs). We hypothesized that KMT2C/D loss-of-function (LOF) mutations may associate with PD-L1 expression and be a predictor for ICIs efficacy. Therefore, we explored the correlation between KMT2C/D LOF mutations and benefit from ICIs in solid tumors.

Methods: A total of 3396 patients were enrolled in our center. The following solid tumor types were selected: NSCLC (n=1080), colorectal cancer (n=509), gastric cancer (n=269), bile duct cancer (n=122), pancreatic cancer (n=199), hepatocellular carcinoma (n=309), glioma (n=778), melanoma (130). Targeted next-generation sequencing was used to determine mutations and PD-L1 expression was assessed by immunohistochemistry assay (22C3 antibody). An ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was used for exploring the correlation between KMT2C/D LOF and ICIs efficacy. TCGA cohorts were also used. We classified the patients into two groups: KMT2C/D LOF (any truncating mutation) and non-LOF.

Results: Among all patients in our cohort, 36.4% of patients had PD-L1 expression (TPS&gt;10%) in the LOF group, while 23.6% of patients had PD-L1 expression in the non-LOF group (P = 0.012). However, the correlations of KMT2C/D LOF mutations with PD-L1 expression were only observed in colorectal cancer (P = 0.031) and NSCLC (P = 0.047), but not in other cancer types. In TCGA colorectal cancer cohort, the median PD-L1 expression was significantly higher in the LOF group (1.47 vs 0.60, P &lt; 0.0001). There was a trend suggesting that median PD-L1 expression in the LOF group was higher in NSCLC (P = 0.0754). In addition, there were no correlations between KMT2C/D LOF mutations and PD-L1 expression in other cancer types for TCGA cohorts. In MSKCC cohort, colorectal cancer patients in the LOF group had significantly longer median overall survival (OS) after ICIs therapy (34 vs 13 months, P = 0.0485). Furthermore, the median OS was also higher in the LOF group compared with the non-LOF group in NSCLC (undefined vs 12 months, P = 0.05). Consistently, we did not see the benefit from ICIs for patients in the LOF group in other cancer types.

Conclusions: Our data indicated that KMT2C/D LOF mutations were correlated with PD-L1 expression in colorectal cancer and NSCLC. Furthermore, KMT2C/D LOF mutations were also associated with better response to ICIs in colorectal cancer and NSCLC, suggesting that KMT2C/D LOF mutations can be as a useful predictor for ICIs efficacy in these two types of cancer.

Citation Format: Naixin Liang, Yanling Niu, Tonghui Ma, Xin Zhang. Correlation of KMT2C/D loss-of-function mutations with PD-L1 expression and response to immune checkpoint inhibitors in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1639.