Fig. 8

Cancer intrinsic molecular alterations and the TIM. (A) Upregulated WNT/beta catenin pathways in CCOs with an immuno-desert microenvironment of primary tumor. (B) Correlation between the total immune score (CIBERSORT) and APC mutation status (Spearman’s correlation test). (C) The KRAS mutation is enriched in tumors with low cytotoxic lymphocyte infiltration (10,000 permutated test and Wilcoxon rank-sum test one-sided). (D) Association between TP53 GOF mutations and decreased cytotoxic lymphocyte infiltration (10,000 random permutation test and Spearman’s correlation test). (E) Upregulated cancer-intrinsic pathways in CCOs with exhausted TIM of primary tumor (GSEA analysis). (F) Frequent FBXW7 mutation in CCOs with exhausted TIM of primary tumor (Fisher’s exact test). CD8⁺ T cell exhaustion score (G) and unfolded protein response pathway score (H) by GSVA analysis based on FBXW7 mutation status (Spearman’s correlation test). (I) FBXW7 mutation and hypermutated phenotype including MSI-H were independently associated with exhausted TIM of primary tumor (multivariate logistic regression analysis). GOF, gain-of-function; TIM, tumor immune microenvironment; CCO, colorectal cancer organoid. MSI-H, microsatellite instability-high