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Impact of chemical-induced mutational load increase on immune checkpoint therapy in poorly responsive murine tumors
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2018-02-26 , DOI: 10.1158/1535-7163.mct-17-1091
Elizabeth A. Kuczynski , Janna Krueger , Annabelle Chow , Ping Xu , Shan Man , Yogi Sundaravadanam , Jessica K. Miller , Paul M. Krzyzanowski , Robert S. Kerbel

A recurring historic finding in cancer drug development is encouraging antitumor effects observed in tumor-bearing mice that fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26, and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26, and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Although tumor PD-L1 expression was upregulated in in vivo chemotherapy-exposed variants, PD-L1 expression levels were not consistently associated with anti-PD-L1 treatment activity across mutagenized or chemotherapy-exposed variants. In summary, mutagenized and more immunogenic mouse tumors were not universally sensitized to PD-L1 blockade. Chemically mutagenized variants may be useful to evaluate the impact of immunologically “hot” or “cold” tumors with a high mutational load, to which certain chemotherapy agents may contribute, on immunotherapy outcomes. Mol Cancer Ther; 17(4); 869–82. ©2018 AACR.

中文翻译:

化学诱导的突变负荷增加对低反应性鼠肿瘤免疫检查点治疗的影响

在癌症药物开发中反复出现的历史性发现令人鼓舞在荷瘤小鼠中观察到的抗肿瘤作用未能转化为临床。这种模式的一个有趣的例外是免疫检查点治疗,因为在癌症患者亚组中观察到的持续肿瘤消退在小鼠中很少见。考虑到这可能部分是由于小鼠肿瘤的突变负荷相对较低,我们在体外用甲基硝基亚硝基胍 (MNNG) 或甲基磺酸乙酯诱变了可移植的小鼠肿瘤细胞系 EMT-6/P、B16F1、RENCA、CT26 和 MC38 (EMS) 并测试了它们对 PD-L1 阻断的反应。外显子组测序证实了诱变剂治疗导致体细胞突变增加,这种效应在体内长期暴露于顺铂或环磷酰胺的 EMT-6 变体中得到了模拟。B16F1 的某些诱变变体,EMT-6/P、CT26 和 MC38(但不是 RENCA)比它们的父母更具免疫原性,但抗 PD-L1 致敏仅在某些 EMT-6/P 和 B16F1 变体中产生。治疗反应模式对应于免疫细胞浸润的变化,尤其是 CD8+ T 细胞的增加。长期暴露于顺铂的 EMT-6 变体也对抗 PD-L1 疗法更敏感。尽管在体内暴露于化疗的变体中肿瘤 PD-L1 表达上调,但 PD-L1 表达水平与跨诱变或暴露于化疗的变体的抗 PD-L1 治疗活性并非始终相关。总之,诱变和更具免疫原性的小鼠肿瘤并非普遍对 PD-L1 阻断敏感。化学诱变变体可能有助于评估具有高突变负荷的免疫“热”或“冷”肿瘤对免疫治疗结果的影响,某些化疗药物可能对此有所贡献。摩尔癌症治疗; 17(4); 869-82。©2018 AACR。
更新日期:2018-02-26
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