致癌物暴露通过阻断免疫抑制性肿瘤微环境的发展来增强癌症免疫原性

中文摘要：

致癌物暴露与癌症免疫原性增强密切相关。已提出肿瘤突变负荷增加和由此产生的新抗原生成与致癌物暴露与癌症免疫原性有关。然而，致癌物暴露对癌症的新抗原非依赖性免疫学影响尚不清楚。在这里，我们证明暴露于化学致癌物的癌细胞无法建立免疫抑制性肿瘤微环境 （TME），导致其 T 细胞介导的体内排斥反应。在小鼠中，缺乏任何额外编码区突变（即新抗原）的化学致癌物处理的乳腺癌细胞克隆以 T 细胞依赖性方式被排斥。引人注目的是，共同注射经致癌物和对照处理的癌细胞阻止了这种排斥反应，这表明免疫抑制性 TME 的丧失是排斥反应的主要原因。致癌物处理的癌细胞降低 M-CSF 表达显着抑制肿瘤相关巨噬细胞 （TAM） 并导致免疫抑制 TME 的丢失。人类肺癌的单细胞分析显示，与从未吸烟的个体相比，前吸烟者的免疫抑制性 TAM 显着减少。这些发现表明，致癌物暴露会损害免疫抑制性 TME 的发展，并表明致癌物与癌症免疫原性之间存在新的联系。

英文摘要：

Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed to link carcinogen exposure and cancer immunogenicity. However, the neoantigen-independent immunological impact of carcinogen exposure on cancer is unknown. Here, we demonstrate that chemical carcinogen-exposed cancer cells fail to establish an immunosuppressive tumor microenvironment (TME), resulting in their T cell–mediated rejection in vivo. A chemical carcinogen-treated breast cancer cell clone that lacked any additional coding region mutations (i.e., neoantigen) was rejected in mice in a T cell–dependent manner. Strikingly, the coinjection of carcinogen- and control-treated cancer cells prevented this rejection, suggesting that the loss of immunosuppressive TME was the dominant cause of rejection. Reduced M-CSF expression by carcinogen-treated cancer cells significantly suppressed tumor-associated macrophages (TAMs) and resulted in the loss of an immunosuppressive TME. Single-cell analysis of human lung cancers revealed a significant reduction in the immunosuppressive TAMs in former smokers compared with individuals who had never smoked. These findings demonstrate that carcinogen exposure impairs the development of an immunosuppressive TME and indicate a novel link between carcinogens and cancer immunogenicity.

论文信息：

论文题目： Carcinogen exposure enhances cancer immunogenicity by blocking the development of an immunosuppressive tumor microenvironment

期刊名称：J Clin Invest.  

时间期卷：2023;133(20):e166494.

在线时间：2023年10月6日

DOI：doi.org/10.1172/JCI166494.

产品信息：

货号：CP-005-005

规格：5ml+5ml

品牌：Liposoma

产地：荷兰

名称：Clodronate Liposomes and Control Liposomes

办事处：Target Technology（靶点科技）

Clodronate Liposomes氯膦酸盐脂质体助力致癌物暴露与癌症模型巨噬细胞研究，荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于JCI：

Liposoma巨噬细胞清除剂ClodronateLiposomes氯膦酸二钠脂质体的材料和方法：

巨噬细胞清除剂ClodronateLiposomes氯膦酸二钠脂质体给药方案和实验结果：

DMSO3-1 tumor growth in WT C57BL/6 mice treated with clodronate liposome versus control liposome(Liposoma). Liposome i.p. injections were performed on days 1, 3, 10, and 17 after tumor inoculation (red arrows, n = 6 per group)。

注射方式：腹腔注射

注射次数：4次

注射时间点：接种后Day1, Day3，Day10，Day17（见红色向下箭头）