致癌物暴露通過阻斷免疫抑制性腫瘤微環(huán)境的發(fā)展來增強癌癥免疫原性

中文摘要：

致癌物暴露與癌癥免疫原性增強密切相關(guān)。已提出腫瘤突變負(fù)荷增加和由此產(chǎn)生的新抗原生成與致癌物暴露與癌癥免疫原性有關(guān)。然而，致癌物暴露對癌癥的新抗原非依賴性免疫學(xué)影響尚不清楚。在這里，我們證明暴露于化學(xué)致癌物的癌細(xì)胞無法建立免疫抑制性腫瘤微環(huán)境 （TME），導(dǎo)致其 T 細(xì)胞介導(dǎo)的體內(nèi)排斥反應(yīng)。在小鼠中，缺乏任何額外編碼區(qū)突變（即新抗原）的化學(xué)致癌物處理的乳腺癌細(xì)胞克隆以 T 細(xì)胞依賴性方式被排斥。引人注目的是，共同注射經(jīng)致癌物和對照處理的癌細(xì)胞阻止了這種排斥反應(yīng)，這表明免疫抑制性 TME 的喪失是排斥反應(yīng)的主要原因。致癌物處理的癌細(xì)胞降低 M-CSF 表達(dá)顯著抑制腫瘤相關(guān)巨噬細(xì)胞 （TAM） 并導(dǎo)致免疫抑制 TME 的丟失。人類肺癌的單細(xì)胞分析顯示，與從未吸煙的個體相比，前吸煙者的免疫抑制性 TAM 顯著減少。這些發(fā)現(xiàn)表明，致癌物暴露會損害免疫抑制性 TME 的發(fā)展，并表明致癌物與癌癥免疫原性之間存在新的聯(lián)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.

論文信息：

論文題目： Carcinogen exposure enhances cancer immunogenicity by blocking the development of an immunosuppressive tumor microenvironment

期刊名稱：J Clin Invest.  

時間期卷：2023;133(20):e166494.

在線時間：2023年10月6日

DOI：doi.org/10.1172/JCI166494.

產(chǎn)品信息：

貨號：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology（靶點科技）

Clodronate Liposomes氯膦酸鹽脂質(zhì)體助力致癌物暴露與癌癥模型巨噬細(xì)胞研究，荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見刊于JCI：

Liposoma巨噬細(xì)胞清除劑ClodronateLiposomes氯膦酸二鈉脂質(zhì)體的材料和方法：

巨噬細(xì)胞清除劑ClodronateLiposomes氯膦酸二鈉脂質(zhì)體給藥方案和實驗結(jié)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

注射次數(shù)：4次

注射時間點：接種后Day1, Day3，Day10，Day17（見紅色向下箭頭）