Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma
Emilien Loeuillard, … , Haidong Dong, Sumera Ilyas
Emilien Loeuillard, … , Haidong Dong, Sumera Ilyas
Published July 14, 2020
Citation Information: J Clin Invest. 2020;130(10):5380-5396. https://doi.org/10.1172/JCI137110.
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Research Article Gastroenterology Oncology Article has an altmetric score of 26

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

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 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.

Authors

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

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Figure 4

TAM blockade promotes a compensatory infiltration of G-MDSCs.

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TAM blockade promotes a compensatory infiltration of G-MDSCs. (A–F and I...
(A–F and I) Tumor growth of 28 days after orthotopic implantation of 1 × 106 SB (murine CCA) cells in WT or Ccr2–/– mouse livers. (A) Average tumor weights in mg of WT and Ccr2–/– mice (n = 12). (B) Percentage of PD-L1+Clec4F+ resident TAMs of F4/80hi TAMs (CD45+CD11b+F4/80hi) in WT or Ccr2–/– tumors (n = 14). Representative flow plots show expression of Clec4F and PD-L1 in F4/80hi TAMs. (C) Percentage of CD11cDimF4/80–CD11b+Gr-1+MDSCs of CD45+ cells in WT or Ccr2–/– tumors (n = 14). (D) Percentage of CD11cDimF4/80–CD11b+Ly6C+ M-MDSCs and CD11cDimF4/80–CD11b+Ly6G+ G-MDSCs of CD45+ cells in Ccr2–/– tumors (n = 4). (E) Schematic of myeloid cell analysis in anti-CSF1R– and control-treated mouse tumors. (F) Average tumor weights in mg of WT mice treated every 3 days from days 14 to 28 (after orthotopic SB cell implantation) with a control rat IgG isotype or anti-mouse CSF1R (AFS98) (n ≥ 7). (G) Heatmap showing average marker expression intensity in the different CyTOF clusters. (H) tSNE plots of CyTOF data sets show different clusters of immune cell populations identified by selected markers. (I) tSNE plots of CyTOF data sets show different clusters of immune cell populations identified by selected markers in tumor from WT mice treated with control IgG (n = 6) or anti-CSF1R (n = 11). Cells are color coded and represent the mean of cell density in each cluster. Black circles outline the G-MDSC cluster (cluster 3). Percentage of G-MDSCs identified by markers expressed in cluster 3 in tumor from WT mice treated with control IgG or anti-CSF1R (n ≥ 6). Data are represented as mean ± SD. One-way ANOVA with Bonferroni’s post hoc test was used. *P < 0.05; ***P < 0.001.