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. 2024 Jun;115(6):1979-1988.
doi: 10.1111/cas.16142. Epub 2024 Mar 15.

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer

Zhuo Cheng  1 , Cheng Yang  2 , Qian Zhao  3 , Jingjiao Zhong  4 , Jin Zhang  5 , Riming Jin  5 , Yao Li  5 , Na Ta  6 , Dong Wu  5 , Zhengang Yuan  1 , Wen Sun  7 , Ruoyu Wang  5
Affiliations

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer

Zhuo Cheng et al. Cancer Sci. 2024 Jun.

Abstract

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

Keywords: PD‐1; PD‐L1; gallbladder cancer; immune checkpoint inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Study flowchart. EHBH, Eastern Hepatobiliary Surgery Hospital; GBC, gallbladder cancer; ICI, immune checkpoint inhibitor; PS, performance status.
FIGURE 2
FIGURE 2
Kaplan–Meier estimates of the (A) progression‐free survival (PFS) and (B) overall survival (OS) of the entire study cohort of gallbladder cancer patients (n = 69). CI, confidence interval.
FIGURE 3
FIGURE 3
Kaplan–Meier curves are shown for progression‐free survival in gallbladder cancer patients stratified by (A) smoking history, (B) alcohol intake history, (C) carcinoma embryonic antigen (CEA) levels, and (D) cutaneous immune‐related adverse events (irAE). HR, hazard ratio.
FIGURE 4
FIGURE 4
(A) Biomarker determinants of response (disease control vs. disease progression) to immune checkpoint inhibitors (ICIs) in patients with gallbladder cancer (GBC). *p < 0.05 (B) Positivity of CD8+ T cells in GBCs from disease control and disease progression groups. (C) Representative images of immune inflamed phenotype in disease control group and immune excluded/desert phenotype in disease progression group are shown with immunohistochemical staining of CD8+ T cells in GBC tissues. The tumor or stroma area was indicated by H&E staining. Scale bar, 100 μm. (D, E) Kaplan–Meier estimates of (D) progression‐free survival and (E) overall survival of patients treated with ICIs in the advanced setting. Patients were stratified by high or low CD8+ T cell‐infiltrated GBCs or different immune phenotypes. HR, hazard ratio; PD‐L1, programmed death 1 ligand 1; SNV, single nucleotide variant; TIL, tumor‐infiltrating lymphocyte; TMB, tumor mutation burden; TPS, tumor proportional score.
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