Targeting the splicing factor SRSF10 in mouse HCC tumors shapes tumor immunity and immunotherapy
The efficacy of immune checkpoint blockade (ICB) therapy in hepatocellular carcinoma (HCC) patients remains poor. This article aims to uncover the role and mechanism of SRSF10 in HCC immunotherapy. SRSF10 is upregulated in a variety of tumors and is associated with poor prognosis. SRSF10 binds to the 3'UTR region of MYB and enhances the stability of MYB RNA levels. This activation leads to increased transcriptional expression of key enzymes associated with glycolysis, such as GLUT1, HK1, and LDHA, resulting in higher lactate content in tumor cells. The lactate in tumor cells inside can increase histone lactylation so as to upregulated the expression of SRSF10. Besides, the lactate produced by tumors promotes lactylation of the histone H3K18la site upon transport into macrophages, which could activate transcription of M2 macrophage genes and increase protumour macrophage activity, so as to creating a suppressive immune microenvironment. Clinically, SRSF10 can be utilized as a biomarker to assess the resistance to immunotherapy in different types of solid tumors. The pharmacological targeting of SRSF10 with 1C8 has been shown to be effective in both murine and human preclinical models. In conclusion, we prove that the SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Overall design: Tumors from WT or shSrsf10 mice were extracted and digested with collagenase type IV (1 mg/ml) and DNase type I (30?U/ml) for 30?min at 37?°C. The cells were filtered through the 70?µm cell strainers, washed with phosphate-buffered saline (PBS), lysed in red blood cell buffer, and resuspended in PBS. Cells were sorted by FACSAria Fusion Flow Cytometer (BD Biosciences). The cell suspension (300-600 living cells per microliter) was loaded onto the Chromium single cell controller (10 x Genomics) to generate single-cell gel beads in the emulsion according to the manufacturer's protocol. Libraries were subsequently prepared sing Single Cell 5'Library and Gel Bead Kit and sequenced on an Illumina NovaSeq 6000 instrument with pair-end 100?bp (PE100) reading strategy.