Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment
Amy J. Petty, … , Xiaopei Huang, Yiping Yang
Amy J. Petty, … , Xiaopei Huang, Yiping Yang
Published October 22, 2019
Citation Information: J Clin Invest. 2019;129(12):5151-5162. https://doi.org/10.1172/JCI128644.
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Research Article Immunology

Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment

Abstract

Tumor-associated macrophages (TAMs) usually display an antiinflammatory M2-like phenotype to facilitate tumor growth. However, what drives M2 polarization of TAMs and how TAMs suppress antitumor immunity within the tumor microenvironment (TME) remain largely undefined. Using several murine tumor models, we showed that hedgehog (Hh) signaling in myeloid cells is critical for TAM M2 polarization and tumor growth. We also found that tumor cells secrete sonic hedgehog (SHH), an Hh ligand, and that tumor-derived SHH drives TAM M2 polarization. Furthermore, Hh-induced functional polarization in TAMs suppresses CD8+ T cell recruitment to the TME through the inhibition of CXCL9 and CXCL10 production by TAMs. Last, we demonstrated that Krüppel-like factor 4 (Klf4) mediates Hh-dependent TAM M2 polarization and the immunosuppressive function. Collectively, these findings highlight a critical role for tumor-derived SHH in promoting TAM M2 polarization, a mechanism for TAM-mediated immunosuppression, and may provide insights into the design of new cancer immunotherapeutic strategies.

Authors

Amy J. Petty, Ang Li, Xinyi Wang, Rui Dai, Benjamin Heyman, David Hsu, Xiaopei Huang, Yiping Yang

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Figure 2

Loss of Hh signaling in myeloid cells suppresses M2 polarization of TAMs and promotes survival in autochthonous HCC.

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Loss of Hh signaling in myeloid cells suppresses M2 polarization of TAMs...
(A) Representative gross image of Smofl/flMdr2–/– and SmoΔMMdr2–/– mice at 12 months after birth. Tumor number and tumor area were quantified by counting and measuring of neoplastic nodules per H&E-stained liver sample. (B) Kaplan-Meier survival curve for the 2 mouse cohorts, Smofl/flMdr2–/– and SmoΔMMdr2–/–. The median survival times were 11.9 months for the Smofl/flMdr2–/– cohort (black line) and 20 months for the SmoΔMMdr2–/– cohort (red line). (C–E) Expression of Arg-1, CD206 (Mrc1), IL-10, and TNF-α in Smofl/flMdr2–/– and SmoΔMMdr2–/– TAMs was measured by qRT-PCR (C), FACS (D), and ELISA (E). Expression of mRNAs was normalized to Actb and compared with that of Smofl/flMdr2–/– TAMs. Values are the mean ± SEM of a minimum of 3 independent experiments. *P < 0.05; **P < 0.005; ***P < 0.0005. n = 8 biological replicates per group (A); n = 15 mice per group (B); n = 5 biological replicates per group (C–E). Two-tailed Student’s t test (A and C–E); log-rank test (B).