Association of KMT2C/D loss‐of‐function variants with response to immune checkpoint blockades in colorectal cancer

Abstract

Immune checkpoint inhibitors (ICIs) have become important treatment strategies, yet responses vary among patients and predictive biomarkers are urgently needed. Mutations in KMT2C and KMT2D lead to increased levels of genomic instability. Therefore, we aimed to examine whether KMT2C/D mutations might be a predictor of immunotherapeutic efficacy. Here, we investigated the associations of KMT2C/D loss‐of‐function (LOF) variants with tumor mutation burden (TMB), MSI‐H, PD‐L1 expression, the levels of tumor‐infiltrating leukocytes (TILs), and clinical response to ICIs. It was found that KMT2C/D LOF variants were associated with higher TMB. Compared with the non‐LOF group, the proportion of patients with MSI‐H tumors was larger in the LOF group. PD‐L1 expression was higher in the LOF group only for colorectal cancer in both the Chinese and The Cancer Genome Atlas cohorts. Importantly, KMT2C/D LOF variants were associated with decreased regulatory T cells and increased levels of CD8+ T cells, activated NK cells, M1 macrophages, and M2 macrophages in colorectal cancer. However, there was no significant association between KMT2C/D LOF and TILs levels in other cancer types. Consistently, the results showed that KMT2C/D LOF variants were associated with prolonged overall survival only in colorectal cancer (p = 0.0485). We also presented that patients with KMT2C/D LOF mutations exhibited a better clinical response to anti‐PD‐1 therapy in a Chinese colorectal cancer cohort (p = 0.002). Taken together, these results suggested that KMT2C/D LOF variants could be a useful predictor for ICIs efficacy in colorectal cancer. In addition, the predictive value of KMT2C/D LOF variants was consistent with their association with TILs levels.

Mappingin silicogenetic networks of theKMT2Dtumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities

“…We not only show that TUBA1B was overexpressed in KMT2D LOF MSI cancers compared to KMT2D WT MSI cancers in two cohorts, TCGA and POG, but we also show that several established ICI response markers are elevated in these cases. Previous studies have shown that a larger proportion of KMT2D LOF cases had durable response to ICI treatment compared to KMT2D WT cases 123,124 , and using TCGA and POG cohorts our results extend this notion to suggest that cases with MSI KMT2D LOF cases would respond more favourably to ICI treatment than MSI KMT2D WT cases. Altogether, these results strongly suggest that KMT2D LOF MSI cancers may respond to ICI treatments, and we thus propose KMT2D as a possible biomarker to further stratify MSI cases for ICI treatment.…”

KMT2 (MLL) family of methyltransferases in head and neck squamous cell carcinoma: A systematic review

“…The potential of KMT2C/D mutations to predict immunotherapy response has been evaluated in other contexts with favorable results, such as in the study by Xie et al that demonstrated KMT2C mutations as an independent factor capable of predicting a better response to anti‐PD‐1 treatments in patients with metastatic melanoma 107 . Liu et al found that KMT2C/D loss‐of‐function variants may be a useful predictor for the effectiveness of ICIs in colorectal cancer 108 …”

“…107 Liu et al found that KMT2C/D loss-of-function variants may be a useful predictor for the effectiveness of ICIs in colorectal cancer. 108 Additionally, other studies linked KMT2C/D mutation/inactivation to better response to PARP1/2 inhibitor therapy, with DNA repairing activity reported. 85,109,110 PARP1/2 inhibitors are shown to be a better approach to target specific DDR in cancer, with good clinical response in many solid tumors, including HNSCC.…”

Understanding the molecular biology of anal squamous cell carcinoma

“…It is also important to consider the tumour microenvironment and see the mutational profiles identified here within the context of tumour‐host interaction, where local immune response (eg, tumour infiltrating lymphocytes [TILs]) 8 or relative hypoxia are seen to play a role. Loss of function KMT2C variants have been associated with response to immune checkpoint blockade in colorectal cancer and were consistent with TILs 9 . It would be interesting to assess TILs in these surgical samples and their association with both outcome and KMT2C status.…”

“…Loss of function KMT2C variants have been associated with response to immune checkpoint blockade in colorectal cancer and were consistent with TILs. 9 It would be interesting to assess TILs in these surgical samples and their association with both outcome and KMT2C status. Interestingly, in colorectal cancer KMT2C was also associated with microsatellite instability (MSI), whereas no patients in this study were MSI high.…”