The molecular landscape of hepatocellular carcinoma (HCC) is characterized by regional heterogeneity in both tumor cells and immune cells within the tumor microenvironment, according to results of a study published in Nature Communications.

Cancer heterogeneity refers to genetic and phenotypic differences occurring in different locations within the same tumor nodule (ie, intratumoral heterogeneity [ITH] revealed through multiregional tumor sampling) or between different tumor nodules from the same patient. Information on ITH can provide insight into the clonal evolutionary processes occurring within the tumor in response to prior treatment.

Nevertheless, previous studies have shown that DNA sequencing of somatic mutations cannot completely characterize the spatiotemporal dynamics of ITH. Furthermore, few of these studies have considered how immune cells in the tumor microenvironment interact with tumor cells during treatment-related cancer evolution.

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“We hypothesize that a better understanding of the interactions between HCC and the immune system can help identify biomarkers of response to [immunotherapy]”, the study authors wrote.

In addition, such an investigation in the setting of HCC provided the opportunity to separately address the contribution of tumor (eg, passenger mutation-related neoepitopes) and viral antigens (ie, hepatitis B viral [HBV] antigens) to adaptive immune system activation.

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To this end, this study involved an integration of data from RNA-sequencing, DNA-sequencing, and T-cell receptor sequencing, as well as DNA copy number changes, performed on 71 specimens (ie, 51 from tumors and 20 from areas adjacent to the tumors) taken from resection specimens from 14 patients with early-stage, treatment-naive HCC; these were spatially mapped.  Single-cell RNA sequencing was also performed on specimens obtained from 7 tumor locations in 2 patients.

One finding from this study, was that ITH, involving neoepitope burden, tumor-infiltrating lymphocyte (TIL) burden and clonality, and HBV expression, was detected in 30% to 40% of the specimens.

While the occurrence of regional differences in the level of TIL was consistent with results from previous studies performed in the setting of HCC, another finding from this study was that regional expression of tumor-specific passenger mutations (ie, neoepitope burden) appeared to contribute to a greater extent to TIL recruitment than the presence of HBV antigens. In addition, different clonal expansion of cells belonging to the adaptive immune system were observed in different regions within the same tumor.

In their concluding remarks, the study authors noted that these results “suggest the complexity of the evolving tumor-immune interactions may contribute to the emergence of ITH.”


Losic B, Craig AJ, Villacorta-Martin C, et al. Intratumoral heterogeneity and clonal evolution in liver cancer. Nat Commun. 2020;11(1):291.