Background Claudin18.2 (CLDN18.2), a tight junction protein highly specific to gastric mucosa, is a promising target for gastric cancer (GC) treatment.1 Immunotherapy targeting PD-1 combined with chemotherapy has been approved as the first line treatment of GC.2 Understanding the expression profiles of CLDN18.2 and PD-L1 could offer guidance for the development of combination therapies that maximize the benefits of both agents. This study investigated the prevalence of CLDN18.2 expression in gastric/gastroesophageal junction (GC/GEJ) adenocarcinoma and its correlation with PD-L1 expression in Chinese patients.
Methods Expression of CLDN18.2 in formalin-fixed, paraffin-embedded (FFPE) GC/GEJ tissue samples was detected by immunohistochemistry (IHC) using an in-house anti-CLDN18.2 antibody (Clone14G11) on the Leica Bond III IHC stainer. Both the staining intensity (0, 1+, 2+, 3+) and the percentage of positive tumor cells were evaluated. CLDN18.2 positivity was defined as expression of CLDN18.2 in ≥ 10% tumor cells with intensity ≥ 1+. Samples with moderate-to-strong CLDN18.2 membrane staining (intensity ≥ 2+) in ≥ 40% tumor cells were also analyzed. PD-L1 expression was assessed based on combined positive score (CPS) using Agilent’s PD-L1 IHC 28–8 pharmDx.
Results A total of 300 GC/GEJ resected tissue samples were assessed, 89 (30%) were histologically classified as intestinal, 158 (52%) diffuse, 33 (11%) mixed, and 20 (7%) others. 295 (98%, 286 GC, 9 GEJ) samples were from primary site, 5 (2%) samples were from metastatic site (ovary, lymph node, omentum or left adnexa). CLDN18.2 staining was positive in 216 (72%), and negative in 84 (28%) of the tissue samples. 136 (45%) samples showed moderate-to-strong CLDN18.2 membrane staining in ≥ 40% tumor cells. CLDN18.2 positivity prevalence was 75% (n = 119/158) in diffuse and 61% (n=54/89) in intestinal subtypes. Moderate-to-strong CLDN18.2 membrane staining in ≥ 40% tumor cells was observed in 48% (n=76/158) diffuse subtypes, and in 39% (n=35/89) intestinal subtypes. For PD-L1 expression, 51 (17%) had PD-L1 CPS ≥ 5. 19% (n=41/216) of the CLDN18.2 positive samples also showed PD-L1 CPS ≥ 5. In the CLDN18.2 subgroup with moderate-to-strong CLDN18.2 membrane staining in ≥ 40% tumor cells, 21% (n=28/136) had PD-L1 CPS≥5. It appears that the distribution of CLDN18.2 expression is independent of PD-L1 status.
Conclusions High prevalence of CLDN18.2 expression in Chinese patients with GC/GEJ adenocarcinoma was observed. About 80% CLDN18.2 positive tumors had PD-L1 CPS < 5. These results support the value of CLDN18.2-targeted therapy in gastric cancer, especially for those patients who may not benefit from anti-PD-1/PD-L1 immuno-checkpoint therapy.
Zhang JW, Dong RL, Shen L. Evaluation and reflection on claudin 18.2 targeting therapy in advanced gastric cancer. Chin J Cancer Res. 2020;32:263–270.
Janjigian YY, Shitara K, Moehler M, et al. Firstline nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastrooesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, openlabel, phase 3 trial. Lancet. 2021;398:27–40.
Ethics Approval This study obtained ethics approval by Shanghai AKM Laboratory Ethics Committee (number: AKMLL202207001).
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.