Analysis of the tumor microenvironment in ineffective patients of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma.
Authors: Kobayashi Kazufumi , Ogasawara Sadahisa , Ishino Takamasa , Unozawa Hidemi , Nakagawa Miyuki , Fujiwara Kisako , Sakuma Takafumi , Fujita Naoto , Kanzaki Hiroaki , Koroki Keisuke , Nakamura Masato , Kiyono Soichiro , Kanogawa Naoya , Kondo Takayuki , Saito Tomoko , Nakagawa Ryo , Nakamoto Shingo , Muroyama Ryosuke , Chiba Tetsuhiro , Kato Naoya 
Published: January 2022

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Background: Atezolizumab plus bevacizumab (Atezo + Bev) has been the standard treatment for frontline systemic therapy in advanced hepatocellular carcinoma (HCC). Immune check point inhibitors and its combination therapies are completely ineffective in some population of patients based on previous reports in several other malignancies. Regarding the results of a phase III trial (IMbrave 150) and several reports from real world practice, ̃20% of patients were determined to be progression disease (PD) as the best radiological response to Atezo + Bev in patients with advanced HCC. In this study, we analyzed the tumor microenvironment using tumor biopsy samples obtained before starting Atezo + Bev to clarify the mechanism of resistance to Atezo + Bev in patients with advanced HCC. Methods: This study enrolled patients with advanced HCC treated with Atezo + Bev at Chiba University Hospital between October 2020 and April 2021. We defined an ineffective group as patients with PD within 2 months according to RECIST version 1.1. The analysis of the tumor microenvironment in this study was performed using the nCounter PanCancer IO 360TM Panel. Results: Of 56 patients who initiated Atezo + Bev during the study period, biopsy samples with a sufficient amount of tumor tissue for analysis were obtained from 30 patients by percutaneous needle biopsy immediately before administering Atezo + Bev. According to radiological assessments, 7 and 23 patients were classified as ineffective and effective groups, respectively. Comparing baseline characteristics of the two groups, the rate of alpha fetoprotein (AFP) ≥ 400 ng/mL was significantly higher in the ineffective group (ineffective group: 85.7%; effective group: 34.8%; p = 0.031). According to gene expression analyses, 101 of 775 genes were differentially expressed between the two groups. Gene set enrichment analysis showed that antigen presentation, cytokine and chemokine signaling, cytotoxicity, immune cell adhesion and migration, and interferon signaling had a lower expression in the ineffective group. Conversely, a higher expression of cell proliferation signaling was observed in the ineffective group. In this cohort, the expression of Wnt signaling showed no significant difference between the two groups. We calculated the cytolytic activity based on the expression of granzyme A and perforin 1, and it was significantly lower in the ineffective group (6.1 in the effective group and 5.3 in the ineffective group, p = 0.013). Conclusions: Analysis of the tumor microenvironment found differences of several gene expressions and those of signaling between the ineffective and effective groups of Atezo + Bev in patients with advanced HCC. The ineffectiveness of Atezo + Bev is due to the reduced action of T cell infiltration and its immune response to tumor.