Abstract 1714P
Background
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with highly heterogeneous cellular components that responds poorly to chemotherapy and immunotherapy. The complete elucidation of the ICC tumor ecosystem is essential for better prognosis and the development of novel treatments.
Methods
We performed a comprehensive profiling of the ICC tumor microenvironment (TME) landscape via single-cell RNA sequencing (scRNA-seq) and proteomics analysis of human ICC samples and analyzed how different cellular components of ICC ecosystem affected patients’ survival.
Results
We found malignant cells and macrophage of ICC formed a dedifferentiation immunosuppression loop, which was important for tumor progression. ICC malignant cells were undergoing dedifferentiation process with increased proliferation capability and tumor-associated macrophages (TAMs) assisted malignant cell dedifferentiation. On the other hand, malignant cells induced immunosuppressive macrophages through induction of myeloid immune checkpoint. Tumor-associated macrophage (TAM) targeting transgenic mouse strain was used to disrupt the dedifferentiation immunosuppression loop in vivo. Targeting the dedifferentiation-immunosuppression loop enhanced T-cell responses against tumors and showed potential as a promising immunotherapy for the treatment of ICC.
Conclusions
We discovered the dedifferentiation-immunosuppression loop between malignant cell and macrophage within the ICC ecosystem based on scRNA-seq and proteomic analysis. Furthermore, we validated TAM targeting strategy to disrupt the dedifferentiation-immunosuppression loop for ICC treatment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
1.National Natural Science Foundation of China; 2.Natural Science Foundation of Zhejiang Province; 3.\"Hundred Talents Plan (Clinical Medicine)\" Foundation of Zhejiang University.
Disclosure
All authors have declared no conflicts of interest.