Targeting tumor-associated macrophages and granulocytic-myeloid-derived suppressor cells augments pd-1 blockade in cholangiocarcinoma

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Abstract

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 that tumor-associated macrophages (TAMs) are the primary source of PD-L1 in human and murine CCA. In a murine model of CCA, recruited PD-L1+ TAMs facilitate 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 novel ApoE G-MDSC subset enriched with TAM blockade; further analysis of a human scRNA-seq dataset 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.

Authors

Emilien Loeuillard, Jingchun Yang, EeeLN Buckarma, Juan Wang, Yuanhang Liu, Caitlin B. Conboy, Kevin D. Pavelko, Ying Li, Daniel O'Brien, Chen Wang, Rondell P. Graham, Rory L. Smoot, Haidong Dong, Sumera Rizvi