Journal Article

Immuno-genomic classification of colorectal cancer organoids reveals cancer cells with intrinsic immunogenic properties associated with patient survival

Chung, Hee Chul, Oh, Ji-Hye, Kim, Minsuh, Chun, Sung-Min, Sung, Chang Ohk, Jo, Daum, Lee, Hyeonjin, Yu, Chang Sik, Jang, Se Jin, Kim, Jihye, Kim, Deokhoon, Kim, Jihun, Lee, Sun-hye, Kim, Tae Won, Cho, Eun Jeong

2021

Overview

Background The intrinsic immuno-ge7nomic characteristics of colorectal cancer cells that affect tumor biology and shape the tumor immune microenvironment (TIM) are unclear. Methods We developed a patient-derived colorectal cancer organoid (CCO) model and performed pairwise analysis of 87 CCOs and their matched primary tumors. The TIM type of the primary tumor was classified as immuno-active, immuno-exhausted, or immuno-desert. Results The gene expression profiles, signaling pathways, major oncogenic mutations, and histology of the CCOs recapitulated those of the primary tumors, but not the TIM of primary tumors. Two distinct intrinsic molecular subgroups of highly proliferative and mesenchymal phenotypes with clinical significance were identified in CCOs with various cancer signaling pathways. CCOs showed variable expression of cancer-specific immune-related genes such as those encoding HLA-I and HLA-II, and molecules involved in immune checkpoint activation/inhibition. Among these genes, the expression of HLA-II in CCOs was associated with favorable patient survival. K-means clustering analysis based on HLA-II expression in CCOs revealed a subgroup of patients, in whom cancer cells exhibited Intrinsically Immunogenic Properties (Ca-IIP), and were characterized by high expression of signatures associated with HLA-I, HLA-II, antigen presentation, and immune stimulation. Patients with the Ca-IIP phenotype had an excellent prognosis, irrespective of age, disease stage, intrinsic molecular type, or TIM status. Ca-IIP was negatively correlated with intrinsic E2F/MYC signaling. Analysis of the correlation between CCO immuno-genotype and TIM phenotype revealed that the TIM phenotype was associated with microsatellite instability, Wnt/β-catenin signaling, APC/KRAS mutations, and the unfolded protein response pathway linked to the FBXW7 mutation in cancer cells. However, Ca-IIP was not associated with the TIM phenotype. Conclusions We identified a Ca-IIP phenotype from a large set of CCOs. Our findings may provide an unprecedented opportunity to develop new strategies for optimal patient stratification in this era of immunotherapy.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Antibodies / Antigens / Apoptosis / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer cells / Cancer Research / Cloning / Cold / Colorectal cancer / Colorectal Neoplasms - immunology / Colorectal Neoplasms - mortality / Female / Gene expression / Genes / Genetic aspects / Genomes / HLA-II, Immuno-genomic / Humans / Immune response / Immunology / Immunotherapy / Intrinsic / Laboratories / Male / Medical equipment and supplies industry / Medical test kit industry / Microenvironment / Oncology / Organoids / Organoids - immunology / Patient outcomes / Prognosis / Stem cells / Survival Analysis