Source: The First Affiliated Hospital
Written by: The First Affiliated Hospital
Edited by: Tan Rongyu, Wang Dongmei

Recently, Prof. Sui Peng’s research group from the First Affiliated Hospital of Sun Yat-sen University published a research paper entitled “The influence of immune heterogeneity on the effectiveness of immune checkpoint inhibitors in multifocal hepatocellular carcinomas” online in Clinical Cancer Research, which deciphered genomic and immune characteristics among tumors with different sizes in multifocal HCC patients through multi-omics analysis and revealed the intertumoral heterogeneous responses to immunotherapy. Ph.D. student Manling Huang is the first author. Prof. Sui Peng and Prof. Lixia Xu are the corresponding authors.

Immunotherapy uses various strategies to enhance anti-tumor immunity and represents a promising option for HCC. However, the overall response rate for the anti-PD-1 treatment in advanced HCC patients is less than 20%. Among those unresponsive patients to anti-PD-1 treatment, a certain proportion have one or more nodules with controllable response, but still shown as progressive disease due to the co-existing progression of other nodules. Recent studies have discussed factors affecting response to immunotherapy, such as microsatellite instability, tumor mutation burdens and intra-tumoral infiltration of CD8+ T cells, but these factors have seldom been compared at nodule-level within the same patient, leaving the mechanisms of intertumoral heterogeneity to immunotherapy poorly understood.

Prof. Sui Peng’s research team performed multi-omics analysis between small tumors and large tumors in 12 multifocal HCC patients (2-7 tumors per patient, 45 tumors in total) through whole genome sequencing, whole exome sequencing and RNA sequencing. They found the small and large tumor of each multifocal HCC patient showed great genomic similarity including identical HBV integrated sites, similar structural variations, mutation profiles and copy number aberrations, indicating that they might be intrahepatic metastases.

They also explored the immune microenvironment of the small and large tumors in multifocal HCC patients and found that the small tumors had higher immune cell infiltration and overexpression of interferon signature predictive of response to anti-PD-1. Moreover, the immune pathways were more vigorous along with less active proliferation pathways in the small tumors. Sia immune class analysis also showed that more small tumors were classified as “Active Immune Response Subtype” than the large tumors, which collectively suggested that the small tumors in multifocal HCC patients had higher immune cell infiltration than the large tumors. They further evaluated the anti-PD-1 treatment responses of nodules with different size in multifocal HCC patients. The result showed that among seven patients who received anti-PD-1 monotherapy, five patients showed various responses to immunotherapy in different nodules. In particular, the small nodule showed better response than the large nodule in the same patient. The findings may partially explain the mixed responses of different tumors to anti-PD-1 treatment.

This work was supported by the National Natural Science Foundation of China, Guangzhou Science, Technology and Innovation Commission, Bureau of Science and Information Technology of Guangzhou Municipality, and Natural Science Foundation of Guangdong Province.

Link to the paper: https://clincancerres.aacrjournals.org/content/early/2020/06/11/1078-0432.CCR-19-3840