m ⁶ A RNA methyltransferases METTL3/14 regulate immune responses to anti‐PD‐1 therapy

Abstract

An impressive clinical success has been observed in treating a variety of cancers using immunotherapy with programmed cell death-1 (PD-1) checkpoint blockade. However, limited response in most patients treated with anti-PD-1 antibodies remains a challenge, requiring better understanding of molecular mechanisms limiting immunotherapy. In colorectal cancer (CRC) resistant to immunotherapy, mismatch-repair-proficient or microsatellite instability-low (pMMR-MSI-L) tumors have low mutation burden and constitute~85% of patients. Here, we show that inhibition of N 6-methyladenosine (m 6 A) mRNA modification by depletion of methyltransferases, Mettl3 and Mettl14, enhanced response to anti-PD-1 treatment in pMMR-MSI-L CRC and melanoma. Mettl3or Mettl14-deficient tumors increased cytotoxic tumor-infiltrating CD8 + T cells and elevated secretion of IFN-c, Cxcl9, and Cxcl10 in tumor microenvironment in vivo. Mechanistically, Mettl3 or Mettl14 loss promoted IFN-c-Stat1-Irf1 signaling through stabilizing the Stat1 and Irf1 mRNA via Ythdf2. Finally, we found a negative correlation between METTL3 or METTL14 and STAT1 in 59 patients with pMMR-MSI-L CRC tumors. Altogether, our findings uncover a new awareness of the function of RNA methylation in adaptive immunity and provide METTL3 and METTL14 as potential therapeutic targets in anticancer immunotherapy.

Roles of RNA Methylation on Tumor Immunity and Clinical Implications

“…In addition, in mismatch-repair-proficient or microsatellite instability-low (pMMR-MSI-L) colorectal cancer and melanoma, the deletion of METTL3 and METTL14 increased the infiltration of CD8+T cells and the secretion of IFN- γ, Cxcl9 and Cxcl10, and enhanced the anti-PD-1 response. The absence of METTL3 and METTL14 reduced the m6A modification of STAT1 and IRF1 mRNA and the YTHDF2-mediated mRNA degradation to increase the levels of STAT1 and IRF1 which participate in IFN- γ-Stat1-Irf1 signal axis and play an important role in anti-PD-1 response ( 110 ).…”

Clinicopathological and immunological characterization of RNA m6A methylation regulators in ovarian cancer

“…The latest studies also revealed the connection between m 6 A regulators and tumor immune-cell infiltration (Han et al, 2019;Li et al, 2020;Wang et al, 2019Wang et al, , 2020Winkler et al, 2019). For example, inhibition of METTL3/14 promoted IFN-γ-STAT1-IRF1 signaling and enhanced response to anti-PD-1 treatment in colorectal cancer (Wang et al, 2020). ALKBH5 inhibitor could heighten the efficacy of cancer immunotherapy (Li et al, 2020).…”

“…The dynamic modification in m 6 A mediated by these regulators not only plays important roles in the development of oocytes and cerebellum but also plays essential roles in regulating cell proliferation and migration, leading to the malignant progression of various cancers and treatment resistance (Chen et al, 2019;Lan et al, 2019). The latest studies also revealed the connection between m 6 A regulators and tumor immune-cell infiltration (Han et al, 2019;Li et al, 2020;Wang et al, 2019Wang et al, , 2020Winkler et al, 2019). For example, inhibition of METTL3/14 promoted IFN-γ-STAT1-IRF1 signaling and enhanced response to anti-PD-1 treatment in colorectal cancer (Wang et al, 2020).…”

The crucial roles of N6-methyladenosine (m6A) modification in the carcinogenesis and progression of colorectal cancer

“…In addition, targeting m 6 A and m 6 A regulators could also be a potential therapeutic strategy for radiotherapy and immunotherapy. A recent study found that the inhibition of METTL3/14 methylation modifications to STAT1 and IRF1 can enhance the sensitivity of anti-PD-1 therapy in pMMR/MSI-L CRC [ 83 ]. So far, no studies have explained the relationship between m 6 A modification and CRC radiotherapy sensitivity.…”