Origin and pharmacological modulation of tumor‐associated regulatory dendritic cells

• Published in: International journal of cancer 2014-06, Vol.134 (11), p.2633-2645
• Main Authors: Zhong, Hua, Gutkin, Dmitriy W., Han, Baohui, Ma, Yang, Keskinov, Anton A., Shurin, Michael R., Shurin, Galina V.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - therapeutic use; Biological and medical sciences; Cancer; Cancer Vaccines - therapeutic use; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - pathology; Carcinoma, Lewis Lung - therapy; Cells, Cultured; dendritic cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - immunology; Flow Cytometry; Immunotherapy; Lung cancer; Lung Neoplasms - immunology; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Male; MDSC; Medical research; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells - cytology; Myeloid Cells - drug effects; Myeloid Cells - immunology; Paclitaxel - therapeutic use; Receptors, Chemokine - metabolism; rho GTP-Binding Proteins - metabolism; small Rho GTPases; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; taxol; Toll-Like Receptor 4 - physiology; tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28590

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. What's new? Cells that suppress the immune response are known be recruited to the tumor microenvironment, and most of these cell types are quite well understood. However, recent studies have indicated that dendritic cells (DCs) can play a similar role. In this study, the authors found that both conventional DCs and MDSCs may actually be reprogrammed by the tumor microenvironment into a tolerogenic state, becoming regulatory DCs (regDCs). They report the molecular mechanism by which this conversion occurs, and show that paclitaxel can prevent it. These results suggest that regDCs may represent a promising therapeutic target.