RTP4 silencing provokes tumor-intrinsic resistance to immune checkpoint blockade in colorectal cancer
RTP4 silencing provokes tumor-intrinsic resistance to immune checkpoint blockade in colorectal cancer
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RTP4沉默引发结直肠癌中肿瘤对免疫检查点阻断的内在抵抗
DOI：
10.1007/s00535-023-01969-w
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发表时间：
2023
影响因子：
6.3
通讯作者：
Tanaka S
中科院分区：
文献类型：
--
作者：
Yamamoto Y;Shimada S;Akiyama Y;Tsukihara S;Sugimoto R;Kabashima A;Tokunaga M;Kinugasa Y;Kawakami Y;Tanaka S
背景免疫检查点阻断（ICB）的最新进展改善了错配修复缺陷和微卫星不稳定性高的结直肠癌（dMMR/MSI-H CRC）患者的预后;然而，PD-1阻断在早期进展性疾病中面临挑战。我们的目的是了解ICB耐药的早期事件，使用体内model.MethodsWe皮下移植的MC 38结肠癌细胞到C57 BL/6小鼠，腹腔注射抗PD-1抗体，然后分离ICB耐药的亚克隆从复发tumors.ResultsComparative基因表达分析发现7个基因显着下调ICB耐药细胞。将敲除7个候选基因的MC 38细胞分别植入抗PD-1抗体处理的C57 BL/6小鼠体内进行致瘤性试验，并对7个候选基因的表达与接受免疫治疗的癌症患者的结局之间的关系进行生物信息学分析，确定干扰素刺激基因和G蛋白偶联受体伴侣蛋白Rtp 4为参与ICB抗性的基因。移植瘤组织的免疫组化分析表明，抗PD-1抗体不能在Rtp 4-KO MC 38细胞中募集T淋巴细胞。结论RTP 4基因的表达可通过组蛋白H3赖氨酸9（H3 K9）甲基化而沉默，RTP 4基因的表达可作为ICB耐药的早期事件，RTP 4基因的表达可作为预测ICB反应的生物标志物，表观遗传学药物与免疫检查点抑制剂联合应用对dMMR/MSI-H结直肠癌可能具有协同作用。
BackgroundRecent advances in immune checkpoint blockade (ICB) have improved patient prognosis in mismatch repair-deficient and microsatellite instability-high colorectal cancer (dMMR/MSI-H CRC); however, PD-1 blockade has faced a challenge in early progressive disease. We aimed to understand the early event in ICB resistance using an in vivo model.MethodsWe subcutaneously transplanted the MC38 colon cancer cells into C57BL/6 mice, intraperitoneally injected anti-PD-1 antibody and then isolated ICB-resistant subclones from the recurrent tumors.ResultsComparative gene expression analysis discovered seven genes significantly downregulated in the ICB-resistant cells. Tumorigenicity assay of the MC38 cells knocked out each of the seven candidate genes into C57BL/6 mice treated with anti-PD-1 antibody and bioinformatics analysis of the relationship between the expression of the seven candidate genes and the outcome of cancer patients receiving immunotherapy identifiedRtp4, an interferon-stimulated gene and a chaperon protein of G protein-coupled receptors, as a gene involved in ICB resistance. Immunohistochemical analysis of transplanted tumor tissues demonstrated that anti-PD-1 antibody failed to recruit T lymphocytes in theRtp4-KO MC38 cells. Mouse and humanRTP4expression could be silenced via histone H3 lysine 9 (H3K9) trimethylation, and public transcriptome data indicated the high expression level ofRTP4in most but not all of dMMR/MSI-H CRC.ConclusionsWe clarified thatRTP4could be silenced by histone H3K9 methylation as the early event of ICB resistance.RTP4expression could be a promising biomarker for predicting ICB response, and the combination of epigenetic drugs and immune checkpoint inhibitors might exhibit synergistic effects on dMMR/MSI-H CRC.
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影响因子：
30.3
作者：
Boys IN;Xu E;Mar KB;De La Cruz-Rivera PC;Eitson JL;Moon B;Schoggins JW
通讯作者：
Schoggins JW
影响因子：
64.8
作者：
Mariathasan S;Turley SJ;Nickles D;Castiglioni A;Yuen K;Wang Y;Kadel EE III;Koeppen H;Astarita JL;Cubas R;Jhunjhunwala S;Banchereau R;Yang Y;Guan Y;Chalouni C;Ziai J;Şenbabaoğlu Y;Santoro S;Sheinson D;Hung J;Giltnane JM;Pierce AA;Mesh K;Lianoglou S;Riegler J;Carano RAD;Eriksson P;Höglund M;Somarriba L;Halligan DL;van der Heijden MS;Loriot Y;Rosenberg JE;Fong L;Mellman I;Chen DS;Green M;Derleth C;Fine GD;Hegde PS;Bourgon R;Powles T
通讯作者：
Powles T
机制驱动的生物标志物指导癌症治疗中的免疫检查点阻断。
DOI：
10.1038/nrc.2016.36
发表时间：
2016-05
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Topalian SL;Taube JM;Anders RA;Pardoll DM
通讯作者：
Pardoll DM
DOI：
10.1016/s1470-2045(17)30422-9
发表时间：
2017-09
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Overman MJ;McDermott R;Leach JL;Lonardi S;Lenz HJ;Morse MA;Desai J;Hill A;Axelson M;Moss RA;Goldberg MV;Cao ZA;Ledeine JM;Maglinte GA;Kopetz S;André T
通讯作者：
André T
DOI：
10.1126/science.1247005
发表时间：
2014-01-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Shalem O;Sanjana NE;Hartenian E;Shi X;Scott DA;Mikkelson T;Heckl D;Ebert BL;Root DE;Doench JG;Zhang F
通讯作者：
Zhang F