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Title: Multiplex immunohistochemistry defines the tumor immune microenvironment and immunotherapeutic outcome in CLDN18.2-positive gastric cancer.
Author: Jia K, Chen Y, Sun Y, Hu Y, Jiao L, Ma J, Yuan J, Qi C, Li Y, Gong J, Gao J, Zhang X, Li J, Zhang C, Shen L.
Journal: BMC Med; 2022 Jul 11; 20(1):223. PubMed ID: 35811317.
Abstract:
BACKGROUND: The FAST study identified claudin-18 (CLDN18.2) as a promising novel therapeutic target for gastric cancer (GC). However, the tumor immune microenvironment and clinicopathological features of CLDN18.2-positive GC are unclear, making it difficult to develop and optimize CLDN18.2-targeted treatments. METHODS: This study included 80 GC patients, 60 of whom received anti-PD-1/PD-L1 treatment. CD4/CD8/CD20/CD66b/CD68/CD163/PD-1/PD-L1/TIM-3/LAG-3/FoxP3/CTLA-4/HLA-DR/STING, and CLDN18.2 were labeled using multiplex immunohistochemistry (m-IHC) to decipher the rate and spatial distribution of T cells, B cells, macrophages, and neutrophils in formalin-fixed, paraffin-embedded tumor tissues isolated from these patients. Tumor immune-microenvironmental features and patient survival stratified by CLDN18.2 expression were analyzed using two independent-sample t-tests and log-rank tests, respectively. RESULTS: We considered moderate-to-strong CLDN18.2 expression ≥ 40% of tumor cells as the cut-off for positivity. The proportion of CD8⁺PD-1^-, CD8⁺LAG-3^-, and CD8⁺TIM-3^- T cells was significantly higher in CLDN18.2-positive tumors than in negative tumors (0.039 vs. 0.026, P = 0.009; 0.050 vs.0.035, P = 0.024; 0.045 vs. 0.032, P = 0.038, respectively). In addition, the number of neutrophils (CD66b⁺) was higher in the CLDN18.2-positive group than in the negative group (0.081 vs. 0.055, P = 0.031, respectively), while the rates of M1 (CD68⁺CD163^-HLA-DR⁺), M2 macrophages (CD68⁺CD163⁺HLA-DR^-), and B cells (CD20⁺) were comparable between the CLDN18.2-positive and negative groups. The average numbers of CD8⁺PD-1^-, CD8⁺LAG-3^-, and CD8⁺TIM-3^-T cells surrounding tumor cells within a 20-μm range were higher in CLDN18.2-positive tumors than in the CLDN18.2-negative tumors (0.16 vs. 0.09, P = 0.011; 0.20 vs. 0.12, P = 0.029; 0.18 vs. 0.12, P = 0.047, respectively). In addition, in the CLDN18.2-positive group, tumor cells surrounded by CD8⁺PD-1^-, CD8⁺LAG-3^- T cells, or M1 macrophages within a 20-μm range accounted for a higher proportion of all tumor cells than those in the CLDN18.2-negative group (10.79% vs. 6.60%, P = 0.015; 12.68% vs. 8.70%, P = 0.049; 9.08% vs. 6.56%, P = 0.033, respectively). These findings suggest that CLDN18.2-positive GC harbors complex immune-microenvironmental features. Additionally, CLDN18.2-positive group had shorter OS and irOS than CLDN18.2-negative group (median OS: 23.33 vs.36.6 months, P < 0.001; median irOS: 10.03 vs. 20.13 months, P = 0.044, respectively). CONCLUSIONS: CLDN18.2-positive GC displayed unique immune-microenvironmental characteristics, which is of great significance for the development of CLDN18.2-targeted therapies. However, the impact of CLDN18.2-related microenvironmental features on prognosis requires further investigation.

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