Role of epidermal growth factor receptor inhibitor-induced interferon pathway signaling in the head and neck squamous cell carcinoma therapeutic response.
Role of epidermal growth factor receptor inhibitor-induced interferon pathway signaling in the head and neck squamous cell carcinoma therapeutic response.
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DOI：
10.1186/s12967-021-02706-8
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发表时间：
2021-01-23
影响因子：
7.4
通讯作者：
Heasley LE
中科院分区：
文献类型：
--
作者：
Korpela SP;Hinz TK;Oweida A;Kim J;Calhoun J;Ferris R;Nemenoff RA;Karam SD;Clambey ET;Heasley LE
表皮生长因子受体（EGFR）在头颈部鳞状细胞癌（HNSCC）中经常扩增或过表达，并且是治疗性抗体西妥昔单抗在这种癌症的管理中的临床验证的靶标。通过肿瘤缩小测量的对EGFR抑制剂的反应程度在HNSCC患者中差异很大，并且HNSCC患者中治疗异质性的生物学机制仍然不明确。用EGFR/ERBB抑制剂吉非替尼和AZD 8931处理EGFR依赖性人和鼠HNSCC细胞系，并进行RNAseq、GSEA和qRT-PCR。通过ELISA和Luminex测定分析条件培养基。通过免疫荧光染色鼠HNSCC肿瘤的T细胞标志物。用单药西妥昔单抗治疗的原发性HSNCC患者标本用Vectra多光谱免疫荧光染色。在一组EGFR依赖性人HNSCC细胞系中测量了对EGFR/ERBB特异性TKI的转录重编程应答，并将干扰素（IFN）α和γ应答确定为顶级TKI诱导途径。尽管药物敏感性相似，但7种细胞系的反应在定量和定性上不同，特别是关于诱导的趋化因子和细胞因子谱。值得注意的是，抗肿瘤趋化因子CXCL 10和促肿瘤因子IL 6表现出广泛且非重叠的诱导。同样，AZD 8931在小鼠B4 B8 HNSCC细胞中表现出强效生长抑制、IFNα/IFNγ途径激活和CXCL 10诱导。与BALB/c小鼠相比，AZD 8931治疗荷原位B4 B8肿瘤的免疫活性小鼠增加了CD 8 + T细胞含量，nu/nu小鼠的治疗应答被消除。最后，在西妥昔单抗单药治疗3-4周之前和之后对HNSCC患者肿瘤的Vectra 3.0分析显示，相对于无应答者，来自表现出治疗应答的患者的标本中的CD 8 + T细胞含量增加。这些发现揭示了HNSCC中异质性、肿瘤细胞内在性、EGFR/ERBB受体诱导的IFN途径激活，并表明个体肿瘤对癌基因靶向药物的反应是直接生长抑制作用和可变诱导的宿主免疫细胞参与的总和。
Epidermal growth factor receptor (EGFR) is frequently amplified or overexpressed in head and neck squamous cell carcinoma (HNSCC) and is a clinically validated target for the therapeutic antibody, cetuximab, in the management of this cancer. The degree of response to EGFR inhibitors measured by tumor shrinkage varies widely among HNSCC patients, and the biological mechanisms that underlie therapeutic heterogeneity amongst HNSCC patients remain ill-defined. EGFR-dependent human and murine HNSCC cell lines were treated with the EGFR/ERBB inhibitors, gefitinib and AZD8931, and submitted to RNAseq, GSEA, and qRT-PCR. Conditioned media was analyzed by ELISA and Luminex assays. Murine HNSCC tumors were stained for T cell markers by immunofluorescence. Primary HSNCC patient specimens treated with single agent cetuximab were stained with Vectra multispectral immunofluorescence. The transcriptional reprogramming response to EGFR/ERBB-specific TKIs was measured in a panel of EGFR-dependent human HNSCC cell lines and interferon (IFN) α and γ responses identified as top-ranked TKI-induced pathways. Despite similar drug sensitivity, responses among 7 cell lines varied quantitatively and qualitatively, especially regarding the induced chemokine and cytokine profiles. Of note, the anti-tumorigenic chemokine, CXCL10, and the pro-tumorigenic factor, IL6, exhibited wide-ranging and non-overlapping induction. Similarly, AZD8931 exerted potent growth inhibition, IFNα/IFNγ pathway activation, and CXCL10 induction in murine B4B8 HNSCC cells. AZD8931 treatment of immune-competent mice bearing orthotopic B4B8 tumors increased CD8 + T cell content and the therapeutic response was abrogated in nu/nu mice relative to BALB/c mice. Finally, Vectra 3.0 analysis of HNSCC patient tumors prior to and after 3–4 weeks of single agent cetuximab treatment revealed increased CD8 + T cell content in specimens from patients exhibiting a therapeutic response relative to non-responders. The findings reveal heterogeneous, tumor cell-intrinsic, EGFR/ERBB inhibitor-induced IFN pathway activation in HNSCC and suggest that individual tumor responses to oncogene-targeted agents are a sum of direct growth inhibitory effects and variably-induced participation of host immune cells.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
3.6
作者：
Hinz, Trista K.;Kleczko, Emily K.;Heasley, Lynn E.
通讯作者：
Heasley, Lynn E.
影响因子：
--
作者：
Egloff AM;Grandis JR
通讯作者：
Grandis JR
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.20517/cdr.2018.12
发表时间：
2018-01-01
期刊：
CANCER DRUG RESISTANCE
影响因子：
--
作者：
Gurule, Natalia J.;Heasley, Lynn E.
通讯作者：
Heasley, Lynn E.