J Liver Cancer.  2020 Sep;20(2):128-134. 10.17998/jlc.20.2.128.

Infiltration of T Cells and Programmed Cell Death Ligand 1-expressing Macrophages as a Potential Predictor of Lenvatinib Response in Hepatocellular Carcinoma

• Sung PS
• Cho SW
• Lee J
• Yang H
• Jang JW
• Bae SH
• Choi JY
• Yoon SK

• KMID: 2508024
• DOI: http://doi.org/10.17998/jlc.20.2.128

Abstract

Background/Aims
Lenvatinib was recently proven to be non-inferior to sorafenib in treating unresectable hepatocellular carcinoma (HCC) in a phase-3 randomized controlled trial. In this study, we investigated whether the response to lenvatinib was affected by tumor immunogenicity.
Methods
Between May 2019 and April 2020, nine patients with intermediate-to-advanced HCC, who were treated with lenvatinib after liver biopsy, were enrolled. Immunohistochemical staining and multi-color flow cytometry were performed on specimens obtained from liver biopsy.
Results
Among the nine patients enrolled, four showed objective responses (complete responses+partial responses). Immunohistochemical staining for CD3, CD68, and programmed cell death ligand 1 (PD-L1) demonstrated that patients with objective responses showed marked infiltration of T cells and PD-L1-expressing macrophages in intra-tumoral and peri-tumoral tissues compared to those without objective responses. A significant difference in the numbers of infiltrated T cells, both in the intra-tumoral (P<0.01) and peri-tumoral regions (P<0.05), were identified between responders and non-responders. Regarding the number of infiltrated macrophages, no significant difference was found between the responders and non-responders, although the number of PD-L1-expressing tumor-associated macrophages was significantly higher in responders than that in non-responders (P<0.05).
Conclusions
Tumor immunogenicity, as indicated by T cell and PD-L1-positive macrophage infiltration, affects lenvatinib response in unresectable HCC.

Keyword

Hepatocellular carcinoma; Lenvatinib; PD-L1; Tumor-associated macrophage; Objective response

Figure

• 

  Figure 1 Objective responses to lenvatinib are associated with intra-tumoral/peri-tumoral infiltration of T cells or programmed cell death ligand 1 (PD-L1)-expressing cells. (A) Frequency of intra-tumoral T cells in lenvatinib responders (n=4) and lenvatinib non-responders (n=5). (B) Frequency of peri-tumoral T cells in lenvatinib responders and lenvatinib non-responders. (C) Frequency of intra-tumoral macrophages in lenvatinib responders and lenvatinib non-responders. (D) Frequency of peri-tumoral macrophages in lenvatinib responders and lenvatinib non-responders. (E) Frequency of PD-L1-expressing cells in lenvatinib responders and lenvatinib non-responders. Bar graphs represent the mean±standard deviation. *P<0.05; †P<0.01.

• 

  Figure 2 Tumor-associated macrophages are the primary cells expressing programmed cell death ligand 1 (PD-L1) in hepatocellular carcinoma after lenvatinib treatment. (A) Immunohistochemistry of CD3, CD68, and PD-L1 in the biopsy specimen of a lenvatinib responder. (B) Flow cytometry analysis of PD-L1, Human Leukocyte Antigen-DR isotype, CD206, and CD163 expression in intra-tumoral macrophages. (C) Immunohistochemistry of CD3, CD68, and PD-L1 in the biopsy specimen of a lenvatinib non-responder.

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