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Imaging features of gadoxetic acid-enhanced MR imaging for evaluation of tumor-infiltrating CD8 cells and PD-L1 expression in hepatocellular carcinoma

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Abstract

Background

Tumor-infiltrating CD8 cells and expression of programmed cell death ligand 1 (PD-L1) are immune checkpoint markers in patients with hepatocellular carcinoma (HCC). We aimed to determine the ability of preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI) findings to predict CD8 cell density and PD-L1 expression in HCC.

Methods

A total of 120 patients with HCC who underwent 3.0-T gadoxetic acid-enhanced MRI before curative resection from January 2016 to June 2020 were enrolled and divided into a training set (n = 84) and a testing set (n = 36). Thirty-four patients with advanced stage HCC who received anti-PD-1 inhibitor between January 2017 and April 2020 and underwent pretreated gadoxetic acid-enhanced MRI scans were enrolled in an independent validation set. PD-L1 expression and CD8 cell infiltration were assessed with immunohistochemical staining, respectively. Two radiologists blinded to pathology results evaluated the pretreated MR features in consensus. Logistic regression and the receiver operating characteristic curve (ROC) analyses were used to determine the value of image features to predict high CD8 cell density, PD-L1 positivity and the combination of high CD8 cell density and PD-L1 positivity in HCC in the training set and validated the findings in the testing set. The associations of MRI predictors with the objective response to immunotherapy were assessed in the independent validation.

Results

In the training set, the independent MRI predictors were irregular tumor margin (ITM, P = 0.008) and peritumoral low signal intensity (PLSI) on hepatobiliary phase (HBP) images (P < 0.001) for PD-L1 positivity, absence of an enhancing capsule (AEC, P = 0.001) and PLSI on HBP images (P = 0.025) for high CD8 cell density, and PLSI on HBP images (P = 0.001) and ITM (P = 0.023) for the both. The area under the curves (AUCs) of the predictive models for evaluating PD-L1 positivity, high CD8 cell density and the combination of high CD8 cell density and PD-L1 positivity were 0.810 and 0.809, 0.740 and 0.728, and 0.809 and 0.874 in the training and testing set, respectively. The objective response was demonstrated to be associated with the combination of PLSI on HBP images and ITM (PHI, P = 0.004), and the combination of PLSI on HBP images and AEC (PHA, P = 0.012) in the independent validation set.

Conclusions

Pretreated MRI features have the potential to identify patients with HCC in an immune-activated state and predict outcomes of immunotherapy.

Trial registration

The study was retrospectively registered on March 5, 2020 with registration no. [2020] 02–012-01.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

AEC:

Absence of enhancing capsule

AP:

Arterial phase

AUC:

Area under the curve

CI:

Confidence interval

CT:

Computed tomography

HBP:

Hepatobiliary phase

HCC:

Hepatocellular carcinoma

ITM:

Irregular tumor margin

LI-RADS:

Liver Imaging Reporting and Data System

MRI:

Magnetic resonance imaging

NLR:

Negative likelihood ratio

OR:

Odds ratio

PD-1:

Programmed cell death protein-1

PD-L1:

Programmed cell death ligand 1

PHA:

The combination of PLSI on HBP images and AEC

PHI:

The combination of PLSI on HBP images and ITM

PLR:

Positive likelihood ratio

PLSI:

Peritumoral low signal intensity

PVP:

Portal venous phase

RECIST:

Response Evaluation Criteria in Solid Tumors

ROC:

Receiver operating characteristic curve

TP:

Transitional phase

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Funding

This study has received funding by National Natural Science Foundation of China grant 91959118 (JW); Science and Technology Program of Guangzhou, China grant number 201704020016 (JW); The Key Research and Development Program of Guangdong Province, 2019B020235002 (JW); SKY Radiology Department International Medical Research Foundation of China Z-2014–07-1912–15 (JW); Guangdong Basic and Applied Basic Research Foundation, 2021A1515010582 (JW) and Clinical Research Foundation of the 3rd Affiliated Hospital of Sun Yat-sen University YHJH201901 (JW).

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Author notes

  1. Lin Sun, Luwen Mu and Jing Zhou contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, People’s Republic of China

    Lin Sun, Wenjie Tang, Linqi Zhang, Sidong Xie, Jingbiao Chen & Jin Wang

  2. Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, People’s Republic of China

    Luwen Mu

  3. Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, People’s Republic of China

    Jing Zhou

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Contributions

Jin Wang, Lin Sun, and Luwen Mu participated in the conception and design of this study. Lin Sun, Luwen Mu, Wenjie Tang, Linqi Zhang, Sidong Xie, and Jingbiao Chen contributed to the selecting of patients and acquisition and analysis and review of the data. Jing Zhou performed all histopathological analyses and participated in the writing of the manuscript. Lin Sun and Luwen Mu analyzed the data and wrote the manuscript. Jin Wang supervised the drafting of the manuscript. All authors critically reviewed each draft and approved the version to be published.

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Correspondence to Jin Wang.

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This retrospective study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards, as reflected by the approval of the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (Date: March 5, 2020/No. [2020] 02–012-01). Patients gave their written consent to usage of their tumor specimen.

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Sun, L., Mu, L., Zhou, J. et al. Imaging features of gadoxetic acid-enhanced MR imaging for evaluation of tumor-infiltrating CD8 cells and PD-L1 expression in hepatocellular carcinoma. Cancer Immunol Immunother 71, 25–38 (2022). https://doi.org/10.1007/s00262-021-02957-w

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