1. CTLA-4 Synergizes With PD1/PD-L1 in the Inhibitory Tumor Microenvironment of Intrahepatic Cholangiocarcinoma
- Author
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Xiao-Jun Guo, Jia-Cheng Lu, Hai-Ying Zeng, Rong Zhou, Qi-Man Sun, Guo-Huan Yang, Yan-Zi Pei, Xian-Long Meng, Ying-Hao Shen, Peng-Fei Zhang, Jia-Bin Cai, Pei-Xin Huang, Ai-Wu Ke, Ying-Hong Shi, Jian Zhou, Jia Fan, Yi Chen, Liu-Xiao Yang, Guo-Ming Shi, and Xiao-Yong Huang
- Subjects
Male ,Oncology ,Lymphocyte ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Kaplan-Meier Estimate ,Lithiasis ,B7-H1 Antigen ,Targeted therapy ,Cholangiocarcinoma ,intrahepatic cholangiocarcinoma ,Tumor Microenvironment ,Immunology and Allergy ,CTLA-4 Antigen ,Intrahepatic Cholangiocarcinoma ,Original Research ,biology ,Liver Diseases ,hepatolithiasis ,FOXP3 ,Forkhead Transcription Factors ,hemic and immune systems ,Middle Aged ,cytotoxic T-lymphocyte-associated antigen-4 ,Neoplasm Proteins ,Up-Regulation ,medicine.anatomical_structure ,Immunohistochemistry ,Female ,programmed death ligand-1 ,medicine.medical_specialty ,Immunology ,chemical and pharmacologic phenomena ,Lymphocytes, Tumor-Infiltrating ,Internal medicine ,PD-L1 ,medicine ,Humans ,Aged ,Proportional Hazards Models ,Tumor microenvironment ,business.industry ,Proportional hazards model ,Gene Expression Profiling ,RC581-607 ,Bile Duct Neoplasms ,biology.protein ,prognosis ,Immunologic diseases. Allergy ,business - Abstract
Intrahepatic cholangiocarcinoma (ICC) is highly invasive and carries high mortality due to limited therapeutic strategies. In other solid tumors, immune checkpoint inhibitors (ICIs) target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD1), and the PD1 ligand PD-L1 has revolutionized treatment and improved outcomes. However, the relationship and clinical significance of CTLA-4 and PD-L1 expression in ICC remains to be addressed. Deciphering CTLA-4 and PD-L1 interactions in ICC enable targeted therapy for this disease. In this study, immunohistochemistry (IHC) was used to detect and quantify CTLA-4, forkhead box protein P3 (FOXP3), and PD-L1 in samples from 290 patients with ICC. The prognostic capabilities of CTLA-4, FOXP3, and PD-L1 expression in ICC were investigated with the Kaplan–Meier method. Independent risk factors related to ICC survival and recurrence were assessed by the Cox proportional hazards models. Here, we identified that CTLA-4+ lymphocyte density was elevated in ICC tumors compared with peritumoral hepatic tissues (P + tumor-infiltrating lymphocytes (TILsCTLA-4 High) showed a reduced overall survival (OS) rate and increased cumulative recurrence rate compared with patients with TILsCTLA-4 Low (P P = .024, respectively). Similarly, patients with high FOXP3+ TILs (TILsFOXP3 High) had poorer prognoses than patients with low FOXP3+ TILs (P = .021, P = .034, respectively), and the density of CTLA-4+ TILs was positively correlated with FOXP3+ TILs (Pearson r = .31, P PD-L1 High) and/or TILsCTLA-4 High presented worse OS and a higher recurrence rate than patients with TILsCTLA-4 LowTumorPD-L1 Low. Moreover, multiple tumors, lymph node metastasis, and high TumorPD-L1/TILsCTLA-4 were independent risk factors of cumulative recurrence and OS for patients after ICC tumor resection. Furthermore, among ICC patients, those with hepatolithiasis had a higher expression of CTLA-4 and worse OS compared with patients with HBV infection or undefined risk factors (P = .018). In conclusion, CTLA-4 is increased in TILs in ICC and has an expression profile distinct from PD1/PD-L1. TumorPD-L1/TILsCTLA-4 is a predictive factor of OS and ICC recurrence, suggesting that combined therapy targeting PD1/PD-L1 and CTLA-4 may be useful in treating patients with ICC.
- Published
- 2021