Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer.
Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer.
复制标题
非小细胞肺癌中表皮生长因子受体的突变激活通过细胞外信号调节激酶下调主要组织相容性复合物I类的表达
DOI：
10.1111/cas.13860
复制
发表时间：
2019-01
期刊：
影响因子：
5.7
通讯作者：
Nakagawa K
中科院分区：
文献类型：
--
作者：
Watanabe S;Hayashi H;Haratani K;Shimizu S;Tanizaki J;Sakai K;Kawakami H;Yonesaka K;Tsurutani J;Togashi Y;Nishio K;Ito A;Nakagawa K
研究发现，程序性细胞死亡-1（PD-1）阻断剂对表皮生长因子受体（EGFR）基因突变呈阳性的非小细胞肺癌（NSCLC）患者的疗效有限，但这种不良反应的潜在机制仍不清楚。鉴于 T 细胞对主要组织相容性复合物 I 类 (MHC-I) 分子呈递的肿瘤抗原的识别对于抗肿瘤免疫反应至关重要，我们研究了 EGFR 酪氨酸激酶抑制剂 (TKI) 对 NSCLC 细胞系中 MHC-I 表达的影响。适当的 EGFR-TKIs 可以增加 EGFR 突变阳性的 NSCLC 细胞（包括具有 T790M 二次突变的细胞）的 mRNA 和细胞表面蛋白水平的 MHC-I 表达。 Trametinib 是细胞外信号调节激酶 (ERK) 激酶 MEK 的抑制剂，也会增加 MHC-I 表达，而磷脂酰肌醇 3 激酶 (PI3K) 抑制剂 buparlisib 则不会，这表明 MEK-ERK 通路介导了 EGFR 激活后 MHC-I 表达的下调。对 EGFR-TKI 治疗前后获得的 EGFR 突变 NSCLC 样本进行的免疫组织化学分析也显示，EGFR 和 ERK 磷酸化形式的下调与 MHC-I 上调相关，浸润性 CD8+ T 细胞数量增加，治疗后 PD-1 配体 1 表达增加。因此，我们的结果表明 EGFR 的突变激活通过 MEK-ERK 通路抑制 NSCLC 中 MHC-I 的表达，从而导致此类肿瘤对免疫治疗的反应不佳。需要进一步的研究来评估 EGFR-MEK-ERK 信号传导与 EGFR 突变 NSCLC 的免疫反应之间的关系。
The efficacy of programmed cell death–1 (PD‐1) blockade in patients with non–small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC‐I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC‐I expression in NSCLC cell lines. Appropriate EGFR‐TKIs increased MHC‐I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal–regulated kinase (ERK) kinase MEK, also increased MHC‐I expression, whereas the phosphatidylinositol 3‐kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK‐ERK pathway mediates the down‐regulation of MHC‐I expression in response to EGFR activation. Immunohistochemical analysis of EGFR‐mutated NSCLC specimens obtained before and after EGFR‐TKI treatment also revealed down‐regulation of phosphorylated forms of EGFR and ERK in association with up‐regulation of MHC‐I, an increased number of infiltrating CD8+ T cells, and increased PD‐1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC‐I expression through the MEK‐ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR‐MEK‐ERK signaling in and the immune response to EGFR‐mutated NSCLC.
登录
查看更多内容
DOI：
10.1158/1078-0432.ccr-15-1125
发表时间：
2016-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Loi S;Dushyanthen S;Beavis PA;Salgado R;Denkert C;Savas P;Combs S;Rimm DL;Giltnane JM;Estrada MV;Sánchez V;Sanders ME;Cook RS;Pilkinton MA;Mallal SA;Wang K;Miller VA;Stephens PJ;Yelensky R;Doimi FD;Gómez H;Ryzhov SV;Darcy PK;Arteaga CL;Balko JM
通讯作者：
Balko JM
DOI：
10.1158/1078-0432.ccr-15-3101
发表时间：
2016-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gainor JF;Shaw AT;Sequist LV;Fu X;Azzoli CG;Piotrowska Z;Huynh TG;Zhao L;Fulton L;Schultz KR;Howe E;Farago AF;Sullivan RJ;Stone JR;Digumarthy S;Moran T;Hata AN;Yagi Y;Yeap BY;Engelman JA;Mino-Kenudson M
通讯作者：
Mino-Kenudson M
影响因子：
32.4
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
通讯作者：
Mellman, Ira
影响因子：
4.3
作者：
Johnson, Douglas B.;Rioth, Matthew J.;Horn, Leora
通讯作者：
Horn, Leora
DOI：
10.1016/s0140-6736(16)32517-x
发表时间：
2017-01-21
期刊：
Lancet (London, England)
影响因子：
--
作者：
Rittmeyer A;Barlesi F;Waterkamp D;Park K;Ciardiello F;von Pawel J;Gadgeel SM;Hida T;Kowalski DM;Dols MC;Cortinovis DL;Leach J;Polikoff J;Barrios C;Kabbinavar F;Frontera OA;De Marinis F;Turna H;Lee JS;Ballinger M;Kowanetz M;He P;Chen DS;Sandler A;Gandara DR;OAK Study Group
通讯作者：
OAK Study Group