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Lenvatinib activates potential anti-tumor immunity by increasing infiltration of immune cells and interferon response in tumor microenvironment of advanced hepatocellular carcinoma
Background
It has been reported that the combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, and an immune checkpoint inhibitor enhances the antitumor activity via tumor immune modulation, and clinical trials of the combination have also been conducted. However, the changes of immuno-oncologic features by lenvatinib are poorly understood clinically. Here we show the effects of lenvatinib on immune status for optimizing the combination therapy in hepatocellular carcinoma (HCC) using clinical samples.
Methods
In a single-center observational study, 51 HCC patients who received lenvatinib monotherapy as a first-line treatment were enrolled. We collected the blood samples (n=51) and the archival tumor tissue (n, pre-treatment/ four weeks after the treatment/ postprogression=50/8/12). RNA extracted from HCC tissue samples were subjected to transcriptome analysis and clustered into two groups by immune status using nCounter PanCancer Tumor Signaling 360 Panel. Then each group was investigated in terms of the dynamics of tumor signaling. We also analyzed longitudinal monitoring of circulating immune proteins and chemokines in peripheral blood using Luminex system.
Results
We firstly classified specimens at baseline according to immune-related gene signatures. Pathway analysis derived into two subtypes, Immune-Hot and Immune-Cold, which were characterized by tumor immune response related signatures including immune evasion and inflammation. The expression levels of some tumor signatures, such as Wnt, MAPK and EGF signaling, differed between the two subtypes, while the levels of VEGF signaling did not differ. Lenvatinib showed the similar anti-tumor efficacy with objective response rate (RECIST 1.1) at around 30% and progression-free survival at around 6 months in both subtypes. It is possible that this result is due to the similar expression levels of VEGF signaling. Next, we evaluated the expression changes between pre and 4-week specimens. On-treatment samples at 4-week showed significant upregulation of immune response related signatures, lymphoid and myeloid cell evasion, inflammation, and interferon response and the degree of these upregulations was greater in Immune-cold subtype. In contrast, signatures related to cell cycle and Notch signaling were simultaneously downregulated. Moreover, Wnt signaling and VEGF signaling were clearly suppressed, which suggests that the efficient VEGF blockade causes a series of immune modification in the study. Luminex analysis displayed the accompanying rise of the level of interferon gamma in peripheral blood at 4-week. While immuno-supportive changes occurred at 4-week, the gene signatures altered toward immunosuppressive condition at post-progression.
Conclusions
These results suggest possible association between lenvatinib and tumor immune system of advanced HCC regardless of the immune status before administration. Our findings could expand the possibility of lenvatinib as a potentiator of immune blockade therapies. With limited number of samples as exploratory analysis, further analysis is required to clarify the details of tumor microenvironment and biomarker research for optimized treatment selection and less invasively diagnosis.
Legal entity responsible for the study
The authors.
Funding
Eisai co., ltd.
Disclosures
Y. Kato: Full / Part-time employment: Eisai Co., Ltd. M. Kimura: Full / Part-time employment: Eisai Co, Ltd. N. Suzuki: Full / Part-time employment: Eisai Co, Ltd. H. Aikata: Honoraria (self): Eisa Co., Ltd; Research grant / Funding (institution): Eisa Co., Ltd. All other authors have declared no conflicts of interest.
