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 3

PD-L1+ TAMs are recruited from the BM in CCA.

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PD-L1+ TAMs are recruited from the BM in CCA. (A–C and E–I) Tumor growth...
(A–C and E–I) Tumor growth of 28 days after orthotopic implantation of 1 × 106 SB (murine CCA) cells in WT or Pd-l1–/– mouse livers. (A) Ratio of recruited TAMs (CD45+CD11b+F4/80intCCR2+) to resident TAMs (CD45+CD11b+F4/80hiClec4F+) in WT mouse liver (from mice without tumors) or SB tumor (n ≥ 11). (B) Percentage of PD-L1+CCR2+ recruited TAMs of F4/80int TAMs (CD45+CD11b+F4/80int) in WT mouse liver, tumor-adjacent liver, or tumor. Representative flow plots show expression of CCR2 and PD-L1 in F4/80int TAMs (n ≥ 7). (C) Percentage of PD-L1+Clec4F+ resident TAMs of F4/80hi TAMs (CD45+CD11b+F4/80hi) in WT mouse liver, tumor-adjacent liver, or tumor. Representative flow plots show expression of Clec4F and PD-L1 in F4/80hi TAMs (n ≥ 7). (D) Schematic of mouse BM transplantation. (E) Average tumor weights in mg of Pd-l1–/–mice transplanted with WT BM (WT–Pd-l1–/–) or WT mice transplanted with Pd-l1–/– BM (Pd-l1–/––WT) (n ≥ 8). (F) Representative photographs of livers from E. (G) Percentage of CCR2+ recruited TAMs of total TAMs (CD45+CD11b+F4/80+) in tumors from WT–Pd-l1–/– or Pd-l1–/––WT mice (n ≥ 7). (H) Percentage of CD8+CD11a+ reactive CTLs of CD45+CD3+ cells in tumors from WT–Pd-l1–/– or Pd-l1–/––WT mice (n ≥ 7). (I) Percentage of granzyme B expressed in CD8+CD11a+ reactive CTLs (CD45+CD3+CD8+ CD11a+) in tumors from WT–Pd-l1–/– or Pd-l1–/––WT mice (n ≥ 7). Data are represented as mean ± SD. Unpaired Student’s t test (A, E, and G–I) and 1-way ANOVA with Bonferroni’s post hoc test (B and C) were used. *P < 0.05; **P < 0.01; ***P < 0.001.