Tumor-derived TGF-β and prostaglandin E2 attenuate anti-tumor immune responses in head and neck squamous cell carcinoma treated with EGFR inhibitor.
Tumor-derived TGF-β and prostaglandin E2 attenuate anti-tumor immune responses in head and neck squamous cell carcinoma treated with EGFR inhibitor.
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DOI：
10.1186/s12967-014-0265-3
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发表时间：
2014-09-21
影响因子：
7.4
通讯作者：
Kobayashi H
中科院分区：
文献类型：
--
作者：
Kumai T;Oikawa K;Aoki N;Kimura S;Harabuchi Y;Celis E;Kobayashi H
egfr靶向治疗是头颈部鳞状细胞癌患者的一个有吸引力的选择。我们最近报道了使用EGFR抑制剂作为辅助治疗来增强肿瘤细胞中的HLA-DR表达，以改善癌症免疫治疗。然而，我们观察到EGFR抑制剂导致抗肿瘤反应降低，而不考虑肿瘤细胞上HLA-DR表达的上调。在这项研究中，我们专门研究了EGFR抑制调节抗肿瘤反应的机制。EGFR抑制剂厄洛替尼被用来评估肿瘤抗原特异性辅助T细胞对抗肿瘤反应的调节。然后，我们检查了EGFR抑制剂的施用是否改变了肿瘤细胞因子谱和肿瘤细胞上免疫相关分子的表达。尽管EGFR抑制可以增强牙龈癌细胞株上HLA-DR的表达，但EGFR反应性辅助性T细胞克隆对肿瘤细胞的抗肿瘤反应减弱。抑制EGFR未改变肿瘤细胞上CD80、CD86或PD-L1的表达。相反，EGFR抑制可增加转化生长因子β (TGF-β)和前列腺素E2的产生，表明这些免疫抑制分子参与了T细胞对肿瘤识别的减弱。值得注意的是，通过添加抗tgf -β抗体或COX2抑制剂，可以逆转EGFR抑制后HTL对肿瘤反应的衰减。靶向TGF-β和前列腺素E2可能会改善联合免疫治疗和EGFR抑制剂治疗的癌症患者的预后。
EGFR-targeted therapy is an attractive option for head and neck squamous cell carcinoma patients. We have recently reported the use of EGFR inhibitors as an adjunct treatment to enhance HLA-DR expression in tumor cells to improve cancer immunotherapy. Nevertheless, we observed that EGFR inhibitors resulted in decreased anti-tumor responses, regardless of upregulation of HLA-DR expression on the tumor cell. In this study, we specifically investigated the mechanisms by which EGFR inhibition modulated anti-tumor responses. An EGFR inhibitor erlotinib was used to assess the modulation of anti-tumor responses by tumor antigen-specific helper T cells. We then examined whether administration of the EGFR inhibitor altered tumor cytokine profiles and expression of immune-related molecules on tumor cells. Despite the augmented HLA-DR expression on a gingival cancer cell line by EGFR inhibition, anti-tumor responses of EGFR reactive helper T cell clones against tumor cells were decreased. EGFR inhibition did not change the expression of CD80, CD86, or PD-L1 on the tumor cells. Conversely, production of transforming growth factor beta (TGF-β) and prostaglandin E2 was increased by EGFR inhibition, indicating that these immunosuppressive molecules were involved in diminishing tumor recognition by T cells. Significantly, attenuation of HTL responses against tumors after EGFR inhibition was reversed by the addition of anti-TGF-β antibody or COX2 inhibitors. Targeting TGF-β and prostaglandin E2 may allow for improved outcomes for cancer patients treated with combination immunotherapy and EGFR inhibitors.
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影响因子：
11.2
作者：
Sharma, S;Yang, SC;Dubinett, SM
通讯作者：
Dubinett, SM
影响因子：
5.8
作者：
Kobayashi, Hiroya;Kumai, Takumi;Celis, Esteban
通讯作者：
Celis, Esteban
影响因子：
11.2
作者：
Mao, Yumeng;Poschke, Isabel;Kiessling, Rolf
通讯作者：
Kiessling, Rolf
DOI：
10.1158/1541-7786.mcr-13-0187
发表时间：
2013-12
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Fletcher EV;Love-Homan L;Sobhakumari A;Feddersen CR;Koch AT;Goel A;Simons AL
通讯作者：
Simons AL
影响因子：
--
作者：
Ahmadi N;Goldman R;Seillier-Moiseiwitsch F;Noone AM;Kosti O;Davidson BJ
通讯作者：
Davidson BJ