It is found that KRAS mutations remodel the N6-methyladenosine (m6A) epitranscriptome to promote immune evasion and highlight METTL3 as a promising therapeutic target.
Abstract
KRAS mutations, present in about 40% of colorectal cancers (CRCs), are strongly associated with an immunosuppressive tumor microenvironment characterized by restricted immune infiltration and poor responses to immunotherapy. Here, we found that KRAS mutations remodel the N6-methyladenosine (m6A) epitranscriptome to promote immune evasion. Methylated RNA immunoprecipitation sequencing revealed that KRAS-mutant cells exhibit increased m6A deposition on CD73 mRNA, enhancing its stability through IGF2BP3. TEAD4-dependent recruitment of the METTL3 methyltransferase complex induced the m6A modification, identifying TEAD4 as a spatial regulator of m6A deposition. Functionally, METTL3 knockdown in KRAS-mutant syngeneic tumors suppressed tumor growth and restored antitumor immunity by increasing CD8⁺ T-cell and NK-cell infiltration in a CD73-dependent manner. Moreover, METTL3 inhibition synergized with anti-PD-1 therapy and a CD73 inhibitor to reduce tumor burden. Together, these findings demonstrate that KRAS-driven m6A remodeling is a key mechanism of immune suppression in CRC and highlight METTL3 as a promising therapeutic target.
Mediator complex kinase CDK8 is identified as a driver of resistance towards KRASG12D inhibition in pancreatic ductal adenocarcinoma (PDAC), promoting stromal remodeling and immunosuppression and CDK8 inhibition in resistant tumors re-primes PDAC to anti-CTLA-4 immunotherapy efficacy.
Kathleen M. McAndrews, Krishnan K. Mahadevan, Bingrui Li et al.· EMBO Journal· 1 citation
The recent approval of covalent KRAS G12C inhibitors, sotorasib and adagrasib, has revealed that targeted KRAS blockade can remodel the TME toward an immunostimulatory state, providing a mechanistic rationale for combining KRAS-directed agents with immune checkpoint blockade, STING agonists, and neoantigen vaccines.
Vasudevan Ramachandran, H. L. Koyou, Siddarth Raajasekar et al.· Frontiers in Oncology· 0 citations
Background The 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. Result The 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-γ 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. Conclusions KMT2D 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.
Timothy En Haw Chan, H. Timmers· bioRxiv· 0 citations
