三阴性乳腺癌(TNBC)代表了乳腺癌的异质性亚型,其特征是由于其侵袭性生物学而导致预后不良。癌相关脂肪细胞(CAAs)在肿瘤的发展中起着积极的作用,侵袭和转移,以及通过分泌各种细胞因子对治疗的反应。CAAs分泌CCL2和ADPN显著影响aPD-1治疗乳腺癌的疗效。我们最近的研究表明橙皮苷,一种天然酚类化合物,显著抑制CCL2,提高CAAs在体外和体内分泌的ADPN,重塑免疫微环境,并增强aPD-1在三阴性乳腺癌中的疗效。我们用油红染色,Bodipy493/503染色和定量实时PCR以验证CAAs的形成。ELISA法检测CAAs分泌的CCL2、ADPN水平。应用流式细胞术和免疫荧光法检测小鼠肿瘤组织中免疫细胞数目的变更。我们的数据表明,橙皮苷PLGA纳米颗粒显着降低CAAs分泌的CCL2和增加ADPN,同时减少了M2巨噬细胞的募集,Tregs和MDSCs在增加CD8+T细胞浸润的同时,M1巨噬细胞和DC进入肿瘤,因此显着增强了aPD-1的体内功效。本研究通过干扰CAAs分泌的CCL2、ADPN,增强免疫治疗的疗效,为临床治疗三阴性乳腺癌提供了新的联合策略。
Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer characterized by an unfavorable prognosis due to its aggressive biology. Cancer-associated adipocytes (CAAs) play an active role in tumor development, invasion and metastasis, and response to treatment by secreting various cytokines. CAAs secrete CCL2 and
ADPN which significantly affect the efficacy of aPD-1 in treating breast cancer. Our recent research has demonstrated that Hesperidin, a natural phenolic compound, significantly inhibits CCL2, elevates
ADPN secreted by CAAs in vitro and in vivo, remodels the immune microenvironment, and potentiates the efficacy of aPD-1 in triple-negative breast cancer. We used Oil red staining, Bodipy 493/503 staining and quantitative real-time PCR to verify the formation of CAAs. ELISA was used to detect levels of CCL2,
ADPN secreted by CAAs. Changes in the number of immune cells in mouse tumor tissues were detected using flow cytometry and immunofluorescence. Our data suggest that Hesperidin PLGA nanoparticles significantly reduced CCL2 and increased
ADPN secreted by CAAs, which concurrently decreased the recruitment of M2 macrophages, Tregs and MDSCs while increased the infiltration of CD8+T cells, M1 macrophages and DCs into tumor, thus significantly potentiated the efficacy of aPD-1 in vivo. This study provides a new combined strategy for the clinical treatment of triple-negative breast cancer by interfering with CCL2,
ADPN secreted by CAAs to enhance the efficacy of immunotherapy.