Origin and pharmacological modulation of tumor-associated regulatory dendritic cells.
Protumorigenic activity of immune regulatory cells has been proven to play a major role in precluding immunosurveillance and limiting the efficacy of anticancer therapies. Although several approaches have been offered to deplete myeloid-derived suppressor cells (MDSC) and regulatory T cells, there are no data on how to control suppressive dendritic cell (DC) accumulation or function in the tumor environment. Although immunosuppressive function of DC in cancer was implicated to immature and plasmacytoid DC, details of how conventional DC (cDC) develop immunosuppressive properties remain less understood. Here, we show that the development of lung cancer in mice was associated with fast accumulation of regulatory DC (regDC) prior to the appearance of MDSC. Using the in vitro and in vivo approaches, we demonstrated that (i)both cDC and MDSC could be polarized into protumor regDC in the lung cancer environment; (ii) cDC → regDC polarization was mediated by the small Rho GTPase signaling, which could be controlled by noncytotoxic doses of paclitaxel; and (iii) prevention of regDC appearance increased the antitumor potential of DC vaccine in lung cancer. These findings not only bring new players to the family of myeloid regulatory cells and provide new targets for cancer therapy, but offer novel insights into the immunomodulatory capacity of chemotherapeutic agents used in low, noncytotoxic doses.
Department of Pulmonary Disease, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
Hua
H
Zhong
Dmitriy W
DW
Gutkin
Baohui
B
Han
Yang
Y
Ma
Anton A
AA
Keskinov
Michael R
MR
Shurin
Galina V
GV
Shurin
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D017239:Paclitaxel / Q000627:therapeutic use*; D019707:Receptors, Chemokine / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000502:physiology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D019496:Cancer Vaccines; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020741:rho GTP-Binding Proteins; D017239:Paclitaxel
MDSC; dendritic cells; small Rho GTPases; taxol; tumor microenvironment