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 1

Loss of Smo in myeloid cells interferes with tumor growth and M2 polarization of TAMs in vivo.

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Loss of Smo in myeloid cells interferes with tumor growth and M2 polariz...
(A) Tumor growth of Hepa1-6 mouse hepatoma cells inoculated s.c. in Smofl/fl and SmoΔM mice. Tumor volumes on day 15 at sacrifice are shown. (B) Arg1, Mrc1, Il10, and Tnf mRNA levels in Smofl/fl and SmoΔM TAMs were measured by qRT-PCR. Expression of mRNAs was normalized to Actb and compared with that of Smofl/fl. (C) Surface CD206 expression and intracellular Arg-1 production in Smofl/fl and SmoΔM TAMs by FACS. (D) TNF-α and IL-10 secretion from Smofl/fl and SmoΔM TAMs was measured by ELISA. Values are mean ± SEM of a minimum of 3 independent experiments. **P < 0.005; ***P < 0.0005. n = 15 mice per group (A); n = 5 biological replicates per group (B–D). Wilcoxon-Mann-Whitney U test (A); 2-tailed Student’s t test (B–D).