Association of intrinsic pathways with altered tumor immune infiltration in hepatocellular carcinoma: New targets for combining immune therapy

Dear Editor, Though cancer immune therapy has achieved benefits in partial patients’ population, the overall responses remain low, and low immune infiltration status has been deemed as a key factor leading to low response.1 In hepatocellular carcinoma (HCC), we found that tumor intrinsic oncogenic pathways were related to tumor infiltrating immune cells: mutation of catenin beta 1 (CTNNB1) or activation of the canonical b-catenin pathway was related to poor immune infiltration, while high expression of Kirsten rat sarcoma viral oncogene homolog (KRAS) was related to a better immune infiltration status, which provides new thoughts on combining immune therapy by targeting tumor intrinsic pathways and gives new markers for preference of treating methods. In this study, we studied changed oncogenic pathways, as well as immune infiltration status of tumors, with bioinformatic methods, using publicly available sequencing data and somatic mutation data in TCGA (LIHC) and ICGC (LIRI JP, LICA FR) databases, which covered HCC patients from different ethics and backgrounds (Supplemental Table S1). After calculation of tumor immune infiltration levels of each patient, we found high immune infiltration levels in HCC tissues could predict better survival of HCC patients, and high Th1 cell tumor infiltration was a consistent good indicator for better survival across different datasets (Figure 1). After clustering of patients according to the Th1 cell score, we found in low Th1 cell infiltration patients, genes, related to adaptive immune response signal transduction and T cell stimulation, were suppressed across datasets, and in those patients, signals of the Wnt/b-catenin pathway and KRAS downregulated genes were highly enriched (Supplemental Figure S1). After matching sequencing data with somatic mutation information, we found that themutation status ofCTNNB1 in HCC patients was related to high expression of CTNNB1 mRNA levels in tumor; in CTNNB1-mutated patients,