Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma
| Autor: | Rondell P. Graham, Caitlin B. Conboy, Daniel R. O'Brien, Yuanhang Liu, Emilien Loeuillard, Rory L. Smoot, Jingchun Yang, Juan Wang, Ying Li, Chen Wang, Kevin D. Pavelko, Sumera Ilyas, Haidong Dong, Eee L.N. Buckarma |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment Chemokine CXCL2 Programmed Cell Death 1 Receptor B7-H1 Antigen law.invention Cholangiocarcinoma 03 medical and health sciences Mice 0302 clinical medicine Cancer immunotherapy law Tumor-Associated Macrophages Tumor Microenvironment Medicine Animals Humans Mice Knockout business.industry Gene Expression Profiling Myeloid-Derived Suppressor Cells Cancer General Medicine medicine.disease Immune checkpoint Blockade Mice Inbred C57BL 030104 developmental biology Bile Duct Neoplasms Tumor progression 030220 oncology & carcinogenesis Myeloid-derived Suppressor Cell Cancer research Suppressor Immunotherapy Single-Cell Analysis business Liver cancer Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | Immune checkpoint blockade (ICB) has revolutionized cancer therapeutics. Desmoplastic malignancies, such as cholangiocarcinoma (CCA), have an abundant tumor immune microenvironment (TIME). However, to date, ICB monotherapy in such malignancies has been ineffective. Herein, we identify tumor-associated macrophages (TAMs) as the primary source of programmed death–ligand 1 (PD-L1) in human and murine CCA. In a murine model of CCA, recruited PD-L1(+) TAMs facilitated CCA progression. However, TAM blockade failed to decrease tumor progression due to a compensatory emergence of granulocytic myeloid-derived suppressor cells (G-MDSCs) that mediated immune escape by impairing T cell response. Single-cell RNA sequencing (scRNA-Seq) of murine tumor G-MDSCs highlighted a unique ApoE G-MDSC subset enriched with TAM blockade; further analysis of a human scRNA-Seq data set demonstrated the presence of a similar G-MDSC subset in human CCA. Finally, dual inhibition of TAMs and G-MDSCs potentiated ICB. In summary, our findings highlight the therapeutic potential of coupling ICB with immunotherapies targeting immunosuppressive myeloid cells in CCA. |
| Databáze: | OpenAIRE |
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