Circulating immune index predicting the prognosis of patients with hepatocellular carcinoma treated with lenvatinib and immunotherapy

De-Zhen Guo; Shi-Yu Zhang; San-Yuan Dong; Jia-Yan Yan; Yu-Peng Wang; Ya Cao; Sheng-Xiang Rao; Jia Fan; Xin-Rong Yang; Ao Huang; Jian Zhou

doi:10.3389/fonc.2023.1109742

Circulating immune index predicting the prognosis of patients with hepatocellular carcinoma treated with lenvatinib and immunotherapy

Front Oncol. 2023 Feb 23:13:1109742. doi: 10.3389/fonc.2023.1109742. eCollection 2023.

Authors

De-Zhen Guo^{1

2}, Shi-Yu Zhang^{1

2}, San-Yuan Dong³, Jia-Yan Yan^{1

2}, Yu-Peng Wang^{1

2}, Ya Cao⁴, Sheng-Xiang Rao³, Jia Fan^{1

2

5}, Xin-Rong Yang^{1

2}, Ao Huang^{1

2}, Jian Zhou^{1

2

5

6}

Affiliations

¹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
² Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China.
⁴ Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, China.
⁵ Institute of Biomedical Sciences, Fudan University, Shanghai, China.
⁶ State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.

Abstract

Background: Immune checkpoint inhibitor (ICI)-based combination therapy has opened a new avenue for the treatment of multiple malignancies including hepatocellular carcinoma (HCC). However, considering the unsatisfactory efficacy, biomarkers are urgently needed to identify the patients most likely to benefit from ICI-based combination therapy.

Methods: A total of 194 patients undergoing ICI-based combination therapy for unresectable HCC were retrospectively enrolled and divided into a training cohort (n = 129) and a validation cohort (n = 65) randomly. A novel circulating immune index (CII) defined as the ratio of white blood cell count (×10⁹/L) to lymphocyte proportion (%) was constructed and its prognostic value was determined and validated.

Results: Patients with CII ≤ 43.1 reported prolonged overall survival (OS) compared to those with CII > 43.1 (median OS: 24.7 vs 15.1 months; 6-, 12-, 18-month OS: 94.2%, 76.7%, 66.1% vs 86.4%, 68.2%, 22.8%, P = 0.019), and CII was identified as an independent prognostic factor for OS (hazard ratio, 2.24; 95% confidence interval, 1.17-4.31; P = 0.015). These results were subsequently verified in the validation cohort. Additionally, patients with low CII levels had improved best radiological tumor response (complete response, partial response, stable disease, progressive disease: 3%, 36%, 50%, 11% vs 0%, 27%, 46%, 27%; P = 0.037) and disease control rate (89% vs 73%; P = 0.031) in the pooled cohort and better pathologic response (pathologic complete response, major pathologic response, partial pathologic response, no pathologic response: 20%, 44%, 28%, 8% vs 0%, 0%, 40%, 60%; P = 0.005) in the neoadjuvant cohort. Detection of lymphocyte subsets revealed that an elevated proportion of CD4+ T cells was related to better OS, while the proportion of CD8+ T cells was not.

Conclusions: We constructed a novel circulating immune biomarker that was capable of predicting OS and therapeutic efficacy for HCC patients undergoing ICI and lenvatinib combination therapy.

Keywords: circulating immune index; hepatocellular carcinoma; immunotherapy; lenvatinib; prognostic models.

Grants and funding

This study was jointly supported by the National Key R&D Program of China (2019YFC1315800, 2019YFC1315802), National Natural Science Foundation of China (No.82150004, 81830102, 81772578, 81802991), Fudan University (IDF152064/014), Zhongshan Hospital Fudan University (2021ZSYQ09), and Shanghai Municipal Key Clinical Specialty.