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Immunomodulatory Effect of Imiquimod Through CCL22

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Immunomodulatory Effect of Imiquimod Through CCL22 ANTICANCER RESEARCH 37 : 3461-3471 (2017) doi:10.21873/anticanres.11714 Immunomodulatory Effect of Imiquimod Through CCL22 Produced by Tumor-associated Macrophages in B16F10 Melanomas SADANORI FURUDATE*, TAKU FUJIMURA*, YUMI KAMBAYASHI, AYA KAKIZAKI, TAKANORI HIDAKA and SETSUYA AIBA Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan Abstract. Background/Aim: Tumor-associated macrophages the tumor site. Conclusion: Our results suggest a possible (TAMs), together with splenic CD11b + cells, help maintain the mechanism for the antitumor immune response induced by tumor microenvironment. The immunomodulatory compound IQM through tumor-associated macrophages. imiquimod (IQM) stimulates innate immune cells, including macrophages, to induce antitumor effects. In order to elucidate Imiquimod (IQM) is an immunomodulatory, small-molecule the effects of IQM on the tumor microenvironment, we compound in the imidazoquinoline family that induces antitumor investigated the immunomodulatory effect of IQM during effects through Toll-like receptor 7 (TLR7). As a TLR7 agonist, melanoma growth by using the B16F10 melanoma model. IQM stimulates innate immunity, including tumor-associated Materials and Methods: To elucidate the immunomodulatory macrophages (TAMs) (1-3). In an experimental murine model, effects of IQM on the tumor microenvironment, we isolated the addition of IQM to cryosurgery increased the cellular CD11b + TAMs and splenic CD11b + cells and evaluated the immune response against tumor antigens, leading to complete immunomodulatory effects of IQM, using the B16F10 rejection of B16OVA melanoma (4). Drobits et al. reported that melanoma model. Results: IQM suppressed B16F10 melanoma the anti-melanoma effect of IQM is dependent on the recruitment growth in parallel with reduction of Foxp3 + regulatory T cells of plasmacytoid dendritic cells (DCs) to the skin through (Tregs) at the tumor site, caused by the down-regulation of chemokine (C-C motif) ligand 2 (CCL2) produced by mast cells CCL22 production by tumor-derived and splenic CD11b + cells. (2). Notably, CCL2 also recruits immature myeloid cells to the Subsequently, we investigated the antitumor or tumor-loading tumor microenvironment (5, 6). Singh et al. reported the effects of splenic CD11b + cells on B16F10 melanoma growth therapeutic effects of a TLR7/8 dual agonist (3M-052) on in vivo. B16F10 melanoma growth was accelerated by splenic B16F10 melanoma in vivo . They concluded that intratumoral CD11b + cells from untreated mice, but was inhibited by splenic administration of 3M-052 significantly suppressed B16F10 CD11b + cells from IQM-treated mice. Consistent with these melanoma growth by increasing CCL2 production from the results, Foxp3 + Tregs were significantly decreased in tumors tumor microenvironment, which might result in induction of M1 of mice implanted with both melanoma and splenic CD11b + macrophages, and even enhanced the therapeutic effect of cells from topical IQM-treated mice. Furthermore, immune checkpoint inhibitors, such as anti-CTLA4 antibody intratumoral administration of anti-CCL22 antibody inhibited (Ab) and anti-PD-L1 Ab (7). B16F10 melanoma growth by decreasing Treg recruitment at In humans, IQM is clinically effective for the treatment of superficial melanomas such as lentigo maligna (8, 9). Several reports have suggested that IQM may be an optimal reagent This article is freely accessible online. for invasive melanoma when used in combination with other therapies (3, 4, 7, 10, 11). Turza et al. reported that IQM was *These Authors contributed equally to this study. effective in 10 cases of superficial dermal and subcutaneous metastasis of melanoma when used in combination with Correspondence to: Taku Fujimura, MD, Ph.D., Department of intralesional interleukin (IL)-2 (9). They concluded that IQM Dermatology, Tohoku University Graduate School of Medicine, 1- could be used to control dermal metastatic melanoma, but 1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. Tel: +81 227177271, Fax: +81 227177361, e-mail: [email protected] that intralesional IL-2 is indispensable for controlling subcutaneous melanoma, suggesting that the abrogation of Key Words: Tumor-associated macrophages, splenic CD11b + cells, regulatory T cell (Treg) function is necessary for induction regulatory T cells, melanoma, imiquimod. of an antitumor immune response by IQM (9). 3461 ANTICANCER RESEARCH 37 : 3461-3471 (2017) CCL22 attracts chemokine (C-C motif) ligand 4 (CCR4) + Germany). DNase1 and lipopolysaccharide (LPS) were purchased T cells, including Tregs, in the lesional skin of melanoma from Sigma (Tokyo, Japan). (12). As Klarquist et al. reported, CCL22-related Tregs drive Tumor inoculation and treatment . B16F10 melanoma cells (100 μl of B16F10 melanoma growth in vivo , and the diversion of 2×10 6 cells/ml) were subcutaneously injected into female C57BL/6 Tregs to normal skin by CCL22 vaccination could limit mice as described previously (13). For quantitative real-time PCR tumor-infiltrating Tregs, subsequently suppressing melanoma (qRT-PCR) and FACS analysis, 5% imiquimod cream was topically growth (12). In addition, as we previously reported, administered on day 7, and the tumor was harvested on day 9. For immunomodulatory drugs such as interferons (IFNs) could qRT-PCR, whole tumors were frozen with liquid nitrogen and then modulate CCL22 production from TAMs to decrease Treg crushed with a Cryo-Press (Microtec, Chiba, Japan). Total RNA was recruitment to the tumor (13). Moreover, another CCR4 extracted by using ISOGEN (Nippon Gene, Tokyo, Japan) according to the manufacturer’s instructions. For FACS analysis, whole tumors ligand, CCL2, is highly produced in the advanced stage of were incubated with collagenase 4 and DNase I for 20 min at 37˚C, ret mouse melanoma (14), suggesting the significance of followed by mechanical disruption, as previously described (13). Treg-related chemokines in melanoma development. These After single-cell suspensions were obtained, FACS analysis was findings suggested that reduction of tumor-derived performed. A total of 1×10 5 cells were re-suspended in PBS/1% FCS chemokines could be a therapeutic target for melanoma. In and incubated with a combination of Abs for 30 min at 4˚C. For the the present study, we examined the therapeutic and detection of Foxp3 expression, cells were fixed and permeabilized by immunomodulatory effects of topical IQM on established using Cytofix/Cytoperm solution (BD Bioscience) according to the manufacturer’s protocol. After washing, the cells were kept in B16F10 melanomas in vivo , focusing on its effects on TAMs, + PBS/1% FCS. For all assays, cells were analyzed by using a C6 flow splenic CD11b cells and Tregs. cytometer (Accuri Cytometers Inc., Ann Arbor, MI, USA). For the therapeutic experiments, the size of established tumors Materials and Methods was measured with a caliper (Mitutoyo, Utsunomiya, Japan), and tumor volume was estimated by using the formula: π/6 × length × Ethics statement for animal experiments . The protocol for the width2. Starting on day 6, imiquimod cream (5%) was topically animal study was approved by the ethics committee of Tohoku administered to the tumors three times a week. Tumor-bearing University Graduate School of Medicine for Animal animals were sacrificed when the tumors displayed severe ulceration Experimentation, Sendai, Japan (Permit number: 2014-153). The or reached a size of 1,000 mm 3. research practices comply with the Tohoku University Graduate School of Medicine’s Animal Experimentation Ethics guidelines and RNA extraction and quantitative real-time PCR experiments. Total policies. All surgeries were performed under sodium pentobarbital RNA was extracted by using an RNeasy Micro kit (Qiagen, anesthesia, and all efforts were made to minimize suffering. Courtaboeuf, France), according to the manufacturer's instructions. RNA was eluted with 14 μl of RNase-free water. Contaminating Animals and the melanoma cell line. C57BL/6 mice and BALB/c genomic DNA was removed with DNase I treatment (RNase-Free mice (5 to 8 weeks old) were purchased from Japan Shizuoka DNase Set; Qiagen). Reverse transcription was performed with the Laboratory Animal Center (Shizuoka, Japan) and housed in the SuperScript VILO cDNA synthesis kit (Invitrogen). Amplification animal facility at the Tohoku University Graduate School of reactions were performed by using an Mx 3000P real-time Medicine. The murine melanoma cell line, B16F10, was obtained quantitative PCR system (Stratagene, Tokyo, Japan). Relative from the American Type Culture Collection (Manassas, VA, USA) mRNA expression levels were calculated for each gene and each and cultured in Dulbecco’s minimal essential medium (Sigma, time point after normalization against GAPDH by using the ΔΔ Ct Tokyo, Japan) supplemented with 10% heat-inactivated fetal calf method. The experiments were repeated at least five times under serum (FCS) (Invitrogen, Tokyo, Japan). All mice were bred under identical conditions. The results are shown as the mean±standard specific pathogen-free conditions at the Tohoku University Graduate deviation (SD) of all experiments. School of Medicine. Purification of CD11b + cells. CD11b + cells were isolated from Reagents. Imiquimod cream (5%) was a kind gift from Mochida tumors and spleens by using MACS beads (Miltenyi, Bergisch- Pharmaceutical Co., Ltd (Tokyo, Japan). Blocking monoclonal Ab Gladbach, Germany), as previously reported (15). Briefly, tumors against mouse CCL22
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