PMID- 31638600
OWN - NLM
STAT- MEDLINE
DCOM- 20200622
LR  - 20211204
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 129
IP  - 12
DP  - 2019 Dec 2
TI  - Hedgehog signaling promotes tumor-associated macrophage polarization to suppress 
      intratumoral CD8+ T cell recruitment.
PG  - 5151-5162
LID - 128644 [pii]
LID - 10.1172/JCI128644 [doi]
AB  - 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 Kruppel-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.
FAU - Petty, Amy J
AU  - Petty AJ
AD  - Department of Pharmacology and Cancer Biology.
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, and.
FAU - Li, Ang
AU  - Li A
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, and.
FAU - Wang, Xinyi
AU  - Wang X
AD  - Department of Pharmacology and Cancer Biology.
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, and.
FAU - Dai, Rui
AU  - Dai R
AD  - Department of Pharmacology and Cancer Biology.
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, and.
FAU - Heyman, Benjamin
AU  - Heyman B
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, and.
FAU - Hsu, David
AU  - Hsu D
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, and.
FAU - Huang, Xiaopei
AU  - Huang X
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, and.
FAU - Yang, Yiping
AU  - Yang Y
AD  - Division of Hematologic Malignancies and Cellular Therapy, Department of 
      Medicine, and.
AD  - Department of Immunology, Duke University, Durham, North Carolina, USA.
LA  - eng
GR  - R01 HL151195/HL/NHLBI NIH HHS/United States
GR  - R01 CA136934/CA/NCI NIH HHS/United States
GR  - R01 CA193167/CA/NCI NIH HHS/United States
GR  - F30 CA213799/CA/NCI NIH HHS/United States
GR  - T32 GM007171/GM/NIGMS NIH HHS/United States
GR  - R21 CA186973/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Cxcr3 protein, mouse)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (KLF4 protein, human)
RN  - 0 (Klf4 protein, mouse)
RN  - 0 (Kruppel-Like Factor 4)
RN  - 0 (Receptors, CXCR3)
RN  - 0 (SHH protein, human)
RN  - 0 (Shh protein, mouse)
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/*cytology
MH  - Carcinoma, Hepatocellular/*immunology
MH  - Cell Line, Tumor
MH  - Cell Lineage
MH  - Female
MH  - HEK293 Cells
MH  - Hedgehog Proteins/*metabolism
MH  - Humans
MH  - Immune Tolerance
MH  - Immunosuppression Therapy
MH  - Kruppel-Like Factor 4
MH  - Liver Neoplasms/*immunology
MH  - Macrophages/*cytology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myeloid Cells/cytology
MH  - Neoplasm Transplantation
MH  - Phenotype
MH  - Receptors, CXCR3/metabolism
MH  - Signal Transduction
MH  - Tumor Microenvironment/immunology
PMC - PMC6877305
OTO - NOTNLM
OT  - Cancer
OT  - Cancer immunotherapy
OT  - Immunology
OT  - Macrophages
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2019/10/23 06:00
MHDA- 2020/06/23 06:00
PMCR- 2020/03/02
CRDT- 2019/10/23 06:00
PHST- 2019/03/06 00:00 [received]
PHST- 2019/08/20 00:00 [accepted]
PHST- 2019/10/23 06:00 [pubmed]
PHST- 2020/06/23 06:00 [medline]
PHST- 2019/10/23 06:00 [entrez]
PHST- 2020/03/02 00:00 [pmc-release]
AID - 128644 [pii]
AID - 10.1172/JCI128644 [doi]
PST - ppublish
SO  - J Clin Invest. 2019 Dec 2;129(12):5151-5162. doi: 10.1172/JCI128644.