Jie Ji1, Peiru Wang1, Qian Zhou1, Lude Zhu1, Haiyan Zhang1, Yunfeng Zhang1, Zhe Zheng1, Anil Kumar Bhatta1, Goulong Zhang2, Xiuli Wang3. 1. Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China. 2. Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: zglamu@163.com. 3. Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: wangxiuli_1400023@tongji.edu.cn.
Abstract
BACKGROUND: Antitumor immunity induced by photodynamic therapy (PDT) is believed to depend on the degree of local and systemic inflammation. The recruitment of leukocytes, in particular by the chemokine CCL8, to the sites of tissue damage has been strongly associated with the initiation of inflammatory reactions. OBJECTIVE: To evaluate whether and how CCL8 enhances the immune response against tumors in 5-aminolevulinic acid (ALA)-mediated PDT. METHODS: In this study, we investigated the effect of ALA-PDT-induced CCL8 expression on the recruitment and polarization of macrophages using immunohistochemistry, western blot and Transwell cell migration assay. We evaluated CCL8 expression following ALA-PDT in vitro and in vivo by using RT-PCR, western blot, and ELISA in clinical cutaneous squamous cell carcinoma (cSCC) samples, a mouse model of cSCC, tumor cells, and macrophages. The effect of the combination of ALA-PDT with CCL8 treatment on anti-tumor immunity was tested in the mouse model. RESULTS: We found that ALA-PDT enhanced CCL8 expression, increased the number of macrophages in tumor, and stimulated their M1 pro-inflammatory phenotype characterized by high expression levels of CD16 and CD80, low expression level of CD163, and absence of CD206 expression. Furthermore, CCL8 enhanced the effect of ALA-PDT on cSCC in mice, such a combination of CCL8 and ALA-PDT had a stronger positive effect in the treatment of mouse cSCC than PDT alone and suppressed tumor volume regrowth. CONCLUSION: ALA-PDT induces CCL8 expression and recruits M1 macrophages, thus suppressing tumor growth.
BACKGROUND: Antitumor immunity induced by photodynamic therapy (PDT) is believed to depend on the degree of local and systemic inflammation. The recruitment of leukocytes, in particular by the chemokine CCL8, to the sites of tissue damage has been strongly associated with the initiation of inflammatory reactions. OBJECTIVE: To evaluate whether and how CCL8 enhances the immune response against tumors in 5-aminolevulinic acid (ALA)-mediated PDT. METHODS: In this study, we investigated the effect of ALA-PDT-induced CCL8 expression on the recruitment and polarization of macrophages using immunohistochemistry, western blot and Transwell cell migration assay. We evaluated CCL8 expression following ALA-PDT in vitro and in vivo by using RT-PCR, western blot, and ELISA in clinical cutaneous squamous cell carcinoma (cSCC) samples, a mouse model of cSCC, tumor cells, and macrophages. The effect of the combination of ALA-PDT with CCL8 treatment on anti-tumor immunity was tested in the mouse model. RESULTS: We found that ALA-PDT enhanced CCL8 expression, increased the number of macrophages in tumor, and stimulated their M1 pro-inflammatory phenotype characterized by high expression levels of CD16 and CD80, low expression level of CD163, and absence of CD206 expression. Furthermore, CCL8 enhanced the effect of ALA-PDT on cSCC in mice, such a combination of CCL8 and ALA-PDT had a stronger positive effect in the treatment of mouse cSCC than PDT alone and suppressed tumor volume regrowth. CONCLUSION:ALA-PDT induces CCL8 expression and recruits M1 macrophages, thus suppressing tumor growth.
Authors: Yeon Sook Choi; Tal H Erlich; Max von Franque; Inbal Rachmin; Jessica L Flesher; Erik B Schiferle; Yi Zhang; Marcello Pereira da Silva; Alva Jiang; Allison S Dobry; Mack Su; Sharon Germana; Sebastian Lacher; Orly Freund; Ezra Feder; Jose L Cortez; Suyeon Ryu; Tamar Babila Propp; Yedidyah Leo Samuels; Labib R Zakka; Marjan Azin; Christin E Burd; Norman E Sharpless; X Shirley Liu; Clifford Meyer; William Gerald Austen; Branko Bojovic; Curtis L Cetrulo; Martin C Mihm; Dave S Hoon; Shadmehr Demehri; Elena B Hawryluk; David E Fisher Journal: Cell Date: 2022-05-12 Impact factor: 66.850