Intratumoral heterogeneity and clonal evolution in liver cancer

Abstract

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCRseq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves singlebiopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.

The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications

“…219 Notably, antitumor immune responses have also been proven to exhibit spatial heterogeneity. 220,221 Reuben et al observed extensive spatial differences in T-cell density and clonality in distinct regions of the same tumors, suggesting substantial intratumoral heterogeneity of the T-cell repertoire. 222 Consistently, Losic et al demonstrated spatial cancer-immune interactions and found that tumor-associated immune infiltrates exhibited regional heterogeneity with distinct tumor regions showing different levels of immune clonal expansion and antigen-specific T-cell responses.…”

“…222 Consistently, Losic et al demonstrated spatial cancer-immune interactions and found that tumor-associated immune infiltrates exhibited regional heterogeneity with distinct tumor regions showing different levels of immune clonal expansion and antigen-specific T-cell responses. 221 The spatial heterogeneity of antitumor immunity may correlate with the intratumoral heterogeneity of cancer cells. Cancer cells are commonly composed of different subclones located in distinct compartmentalized regions that harbor distinct genomic, phenotypic, and antigenic diversities.…”

Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma

“…Recent multiomic analyses have explored and described intensive ITH in TME of HCC 10 . Other recent studies using immunogenomics approach addressed how the immune landscape contributes to genomic-ITH in ovarian cancer 11 and HCC 12 . Despite that, ITH on the immune landscape remains a correlative feature associated with tumour genomic-ITH and its direct clinical impact and role in tumour evolution unexplored.…”

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

“…Heterogeneity is another major characteristic of cancer [11]. It promotes cancer resistance to therapy and even retards immunotherapy responses [53]. Heterogeneity indicates that various types of cells are present in an individual tumor, while a specific signal may play a predominant role in different cells and in different stages of cancer [11,[54][55][56][57][58].…”