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

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 8

Dual inhibition of G-MDSCs and TAMs potentiates anti–PD-1 therapy.

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Dual inhibition of G-MDSCs and TAMs potentiates anti–PD-1 therapy. (A–I)...
(A–I) Tumor growth of 28 days after orthotopic implantation of 1 × 106 SB (murine CCA) cells in WT mice. Mice were treated from day 14 to day 28 after implantation. (A) Survival curves in mice treated with control rat IgG isotype, anti–PD-1 (G4), anti-CSF1R (AFS98), anti-Ly6G (1A8), GW3965 alone, or in the depicted combinations (n ≥ 5). (B) Schematic of mouse immunotherapy treatment and characterization. (C) Representative CT image of liver tumor from a contrast reagent–injected mouse treated with control IgG isotype or anti–PD-1+anti-CSF1R+anti-Ly6G 28 days after implantation. The liver is depicted in blue and the tumor in red. (D) Average tumor weights in mg of WT mice treated with control IgG isotype, anti–PD-1+anti-CSF1R+anti-Ly6G, or anti–PD-1+anti-CSF1R+GW3965 (n ≥ 6) (E) Percentage of PD-L1+ TAMs of F4/80int TAMs (CD45+CD11b+F4/80int) in tumors from WT mice treated with control IgG isotype or anti–PD-1+anti-CSF1R+anti-Ly6G or anti–PD-1+anti-CSF1R+GW3965 (n ≥ 3). (F) Percentage of CD11cDimF4/80–CD11b+Ly6G+ G-MDSCs of CD45+ cells in tumors from WT mice treated with control IgG isotype or anti–PD-1+anti-CSF1R+anti-Ly6G or anti–PD-1+anti-CSF1R+GW3965 (n ≥ 3). (G) Percentage of CD8+ CTLs of CD45+ cells in tumors from WT mice treated with control IgG isotype or anti–PD-1+anti-CSF1R+anti-Ly6G or anti–PD-1+anti-CSF1R+GW3965 (n ≥ 3). (H) Percentage of PD-1+ expressed in CD8+CD11a+ reactive CTLs (CD3+CD8+CD11a+) in tumors from WT mice treated with control IgG isotype or anti–PD-1+anti-CSF1R+anti-Ly6G or anti–PD-1+anti-CSF1R+GW3965 (n ≥ 3). (I) Percentage of granzyme B expressed in CD8+CD11a+ reactive CTLs (CD45+CD3+CD8+CD11a+) in tumors from WT mice treated with control IgG isotype or anti–PD-1+anti-CSF1R+anti-Ly6G or anti–PD-1+anti-CSF1R+GW3965 (n ≥ 3). Data are represented as mean ± SD. The log-rank Mantel-Cox test (A) and ANOVA with Bonferroni’s post hoc test (C–H) were used. *P < 0.05; **P < 0.01; ***P < 0.001.