EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy.
EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy.
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DOI：
10.1038/bjc.2013.577
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发表时间：
2013-10-15
影响因子：
8.8
通讯作者：
Kobayashi, H.
中科院分区：
文献类型：
--
作者：
Kumai, T.;Matsuda, Y.;Oikawa, K.;Aoki, N.;Kimura, S.;Harabuchi, Y.;Celis, E.;Kobayashi, H.
关键词：
头颈部鳞状细胞癌（HNSCC）是全球癌症相关发病和死亡的主要原因。表皮生长因子受体（EGFR）靶向治疗是头颈部鳞状细胞癌传统癌症治疗之外一种有吸引力的策略，但它的疗效仍存在争议。基于T细胞的免疫疗法已被提议作为一种改善头颈部鳞状细胞癌临床结果的新型治疗方法。在这项研究中，我们报道了能诱导针对头颈部鳞状细胞癌的CD4 T细胞反应的人表皮受体（HER）家族表位。这些结果为通过将EGFR靶向治疗与基于T细胞的免疫疗法相结合来治疗头颈部鳞状细胞癌的新策略提供了支持。
我们在体外评估了来自EGFR的预测CD4 T细胞肽表位诱导抗肿瘤免疫反应的能力。此外，还评估了EGFR抑制剂在头颈部鳞状细胞癌细胞系中增强肿瘤MHC II类表达并随后增加T细胞识别的能力。
在几个预测的肽表位中，EGFR875 - 889引发了受HLA - DR4、DR15或DR53分子限制的CD4 T细胞反应，这表明该肽作为一种混杂的T细胞表位起作用。肽反应性T细胞对负载表达EGFR的肿瘤细胞裂解物的自体树突状细胞有反应，表明这些表位是自然加工产生的。此外，CD4 T细胞能够直接识别并杀死表达EGFR和相应HLA II类分子的头颈部鳞状细胞癌细胞。在头颈部鳞状细胞癌患者的血液中可以检测到对EGFR875 - 889表位有反应的T细胞。对EGFR875 - 889有反应的CD4 T细胞也能够识别来自EGFR家族成员HER - 2、HER - 3和c - MET同源区域的几种肽类似物。最后，我们研究了EGFR酪氨酸激酶抑制或EGFR阻断抗体对CD4 T细胞肿瘤反应性的影响。用EGFR抑制剂处理肿瘤细胞增强了对EGFR875 - 889有反应的T细胞对肿瘤的识别，这可能是由于头颈部鳞状细胞癌细胞中HLA - DR表达的上调。
我们鉴定了新的CD4 T细胞EGFR表位，其中，EGFR875 - 889作为一种混杂的辅助性T细胞表位起作用，它能够引发针对表达HER家族成员和c - MET的肿瘤的有效抗肿瘤T细胞反应。这些观察结果应有助于将基于T细胞的免疫疗法转化到临床用于治疗头颈部鳞状细胞癌，并为EGFR抑制、免疫靶向联合治疗提供合理的基础。
Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related morbidity and mortality worldwide. Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. T-cell-based immunotherapy has been proposed as a novel therapeutic approach to improve the clinical outcome for HNSCC. In this study, we report human epidermal receptor (HER) family epitopes that induced CD4 T-cell responses to HNSCC. The results provide support for a novel strategy to treat HNSCC by combining EGFR-targeted therapy with T-cell-based immunotherapy. We evaluated the capacity of predicted CD4 T-cell peptide epitopes from EGFR to induce antitumour immune responses in vitro. In addition, EGFR inhibitors were evaluated for their ability to augment tumour MHC class II expression in HNSCC cell lines and subsequently increase T-cell recognition. Among several predicted peptide epitopes, EGFR875–889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed. In addition, the CD4 T cells were capable of directly recognising and killing HNSCC cells expressing EGFR and the appropriate HLA class II molecule. T cells reactive with the EGFR875–889 epitope could be detected in the blood of HNSCC patients. EGFR875–889-reactive CD4 T cells were also able to recognise several peptide analogues derived from homologous regions of EGFR family members, HER-2, HER-3 and c-MET. Finally, we examined the effects of EGFR tyrosine kinase inhibition or EGFR-blocking antibodies on CD4 T-cell tumour reactivity. Treatment of tumour cells with the EGFR inhibitors enhanced tumour recognition by EGFR875–889-reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells. We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR875–889 functions as a promiscuous helper T-cell epitope that can elicit effective antitumour T-cell responses against tumours expressing HER family members and c-MET. These observations should facilitate the translation of T-cell-based immunotherapy into the clinic for the treatment of HNSCC and provide a rational basis for EGFR inhibition, immune-targeted combination therapy.
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DOI：
10.1158/1078-0432.ccr-12-1555
发表时间：
2013-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Stabile LP;He G;Lui VW;Thomas S;Henry C;Gubish CT;Joyce S;Quesnelle KM;Siegfried JM;Grandis JR
通讯作者：
Grandis JR
影响因子：
11.5
作者：
Learn, CA;Hartzell, TL;Sampson, JH
通讯作者：
Sampson, JH
影响因子：
30.8
作者：
Bell, DW;Gore, I;Haber, DA
通讯作者：
Haber, DA
HLA-A2（+）癌症患者的表皮生长因子受体衍生的肽免疫原性的鉴定。
影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1158/1078-0432.ccr-11-0370
发表时间：
2011-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Quesnelle KM;Grandis JR
通讯作者：
Grandis JR