Association of Hepatobiliary Phase of Gadoxetic-Acid-Enhanced MRI Imaging with Immune Microenvironment and Response to Atezolizumab Plus Bevacizumab Treatment

High intensity of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI imaging (EOB-MRI) in the hepatobiliary phase (HB) is associated with mutations in CTNNB1 and activation of fi-catenin, an immune-cold microenvironment, and an unfavorable response to anti-PD-1/PD-L1 monotherapy in patients with hepatocellular carcinoma (HCC). EOB-MRI could serve as a surrogate marker predicting the immune microenvironment and molecular subtype but does not predict the response to atezolizumab + bevacizumab therapy. Our results suggest that this is because the high-intensity group benefits from bevacizumab, while the low-intensity group benefits from atezolizumab. Although EOB-MRI might serve as a surrogate marker for the response to other currently developed immunotherapies, it is not necessary to avoid atezolizumab + bevacizumab treatment for hyperintense HCC.It has been reported that high intensity in the hepatobiliary (HB) phase of Gd-EOB-DTPAenhanced MRI (EOB-MRI) is associated with an immune-cold microenvironment in HCC. The aim of this study is to reveal whether non-high-intensity HCCs are homogeneous with respect to the immune microenvironment and to investigate the predictive ability of EOB-MRI for the response to atezolizumab + bevacizumab therapy (Atezo/Bev). The association between differences in stepwise signal intensity of HB phase and molecular subtypes and somatic mutations associated with the immune microenvironment was investigated in 65 HCC patients (cohort 1). The association between EOB-MRI and the therapeutic effect of Atezo/Bev was evaluated in the Atezo/Bev cohort (60 patients in cohort 2). The proportion of HCCs having CTNNB1 mutations and classified as Chiang CTNNB1 and Hoshida S3 was high in the high-intensity HB-phase group. Infiltration of tumor-associated macrophages (TAM) and regulatory T-lymphocytes (Treg) was characteristic of the high-intensity and low-intensity groups, respectively. Although EOB-MRI could not predict the response to Atezo/Bev treatment, our results demonstrate that EOB-MRI could serve as a surrogate marker predicting theimmune microenvironment. This suggests that Atezo/Bev treatment can be selected regardless of signal intensity in the EOB-MRI HB phase.

Automated summary

High-intensity Gd-EOB-DTPA-enhanced MRI imaging (EOB-MRI) in the hepatobiliary phase (HB) can predict the immune microenvironment and molecular subtype in hepatocellular carcinoma (HCC) patients but not the response to atezolizumab + bevacizumab therapy. The high-intensity group benefits from bevacizumab, while the low-intensity group benefits from atezolizumab.