Intrahepatic cholangiocarcinoma (iCCA) exhibits extensive intratumoral heterogeneity and extremely high mortality rate. Here, we performed WES, RNA-seq, TCR-seq and multiplexed immunofluorescence on 207 tumor regions from 45 iCCA patients. Over half of iCCA displayed intratumoral heterogeneity of immune infiltration, and iCCA were classified into sparsely, heterogeneously, and highly infiltrated subgroups with distinct immunogenomic characteristics. Sparsely infiltrated tumors displayed active copy number loss of clonal neoantigens and heterogeneous immune infiltration played an important role in the subclonal evolution across tumor subregions. Highly infiltrated tumors were characterized by extensive immune activation and similar TCR repertoire across tumor subregions, but counteracted with T cell exhaustion and pervasive antigen presentation defects. Notably, FGFR2 mutations and fusions correlated with low mutation burden and reduced immune infiltration. Our work sculpted the dynamic tumor-immune interactions and developed a robust classification system to divide iCCA patients into high and low immune evasion groups with different prognosis.
KRAS mutations are causally linked to pro-tumor inflammation and identified as driving factors in tumorigenesis. Here, using multi-omics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS mutant iCCA. In KRAS mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant anti-tumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti-PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in KRAS mutant iCCA patients were significantly associated with superior response to anti-PD-1 immunotherapy.
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