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. 2022 Jan 7;12(1):105.
doi: 10.1038/s41598-021-03706-w.

Soluble programmed cell death-1 predicts hepatocellular carcinoma development during nucleoside analogue treatment

Ritsuzo Kozuka  1 , Masaru Enomoto  2 , Minh Phuong Dong  1 , Hoang Hai  1 , Le Thi Thanh Thuy  1 , Naoshi Odagiri  1 , Kanako Yoshida  1 , Kohei Kotani  1 , Hiroyuki Motoyama  1 , Etsushi Kawamura  1 , Atsushi Hagihara  1 , Hideki Fujii  1 , Sawako Uchida-Kobayashi  1 , Akihiro Tamori  1 , Norifumi Kawada  1
Affiliations

Soluble programmed cell death-1 predicts hepatocellular carcinoma development during nucleoside analogue treatment

Ritsuzo Kozuka et al. Sci Rep. .

Abstract

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

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Conflict of interest statement

In the past year, Dr. Sawako Uchida-Kobayashi has received research funding from Bristol-Myers. The other authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Cumulative rates of hepatocellular carcinoma (HCC) according to (A) soluble inducible T-cell co-stimulator (sICOS), (B) soluble programmed cell death-1 (sPD-1), (C) soluble CD40 (sCD40), and (D) soluble herpes virus entry mediator (sHVEM) levels at baseline.
Figure 2
Figure 2
Cumulative rates of HCC development according to the combination of serum pre-treatment sPD-1 and α-fetoprotein (AFP) levels.
Figure 3
Figure 3
Correlation between the serum sPD-1 level and (A) hepatitis B virus (HBV)-DNA and (B) alanine aminotransferase (ALT) levels. Serum sPD-1 levels in non-cirrhotic and cirrhotic patients (C). Correlation between the serum sPD-1 level and fibrosis-4 (FIB-4) index (D).
Figure 4
Figure 4
Dynamic changes in the serum sPD-1 level in patients who developed HCC during entecavir treatment.
See this image and copyright information in PMC

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