Garrido Greta, Rabasa Ailem, Garrido Cristina, Chao Lisset, Garrido Federico, García-Lora Ángel M, Sánchez-Ramírez Belinda
Tumor Immunology Direction, Molecular Immunology Institute, Center of Molecular Immunology, Havana, Cuba.
Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain.
Front Pharmacol. 2017 Oct 6;8:595. doi: 10.3389/fphar.2017.00595. eCollection 2017.
Defining how epidermal growth factor receptor (EGFR)-targeting therapies influence the immune response is essential to increase their clinical efficacy. A growing emphasis is being placed on immune regulator genes that govern tumor - T cell interactions. Previous studies showed an increase in HLA class I cell surface expression in tumor cell lines treated with anti-EGFR agents. In particular, earlier studies of the anti-EGFR blocking antibody cetuximab, have suggested that increased tumor expression of HLA class I is associated with positive clinical response. We investigated the effect of another commercially available anti-EGFR antibody nimotuzumab on HLA class I expression in tumor cell lines. We observed, for the first time, that nimotuzumab increases HLA class I expression and its effect is associated with a coordinated increase in mRNA levels of the principal antigen processing and presentation components. Moreover, using 7A7 (a specific surrogate antibody against murine EGFR), we obtained results suggesting the importance of the increased MHC-I expression induced by EGFR-targeted therapies display higher in antitumor immune response. 7A7 therapy induced upregulation of tumor MHC-I expression and tumors treated with this antibody display higher susceptibility to CD8 T cells-mediated lysis. Our results represent the first evidence suggesting the importance of the adaptive immunity in nimotuzumab-mediated antitumor activity. More experiments should be conducted in order to elucidate the relevance of this mechanism in cancer patients. This novel immune-related antitumor mechanism mediated by nimotuzumab opens new perspectives for its combination with various immunotherapeutic agents and cancer vaccines.
明确表皮生长因子受体（EGFR）靶向疗法如何影响免疫反应对于提高其临床疗效至关重要。人们越来越重视调控肿瘤与T细胞相互作用的免疫调节基因。先前的研究表明，用抗EGFR药物处理的肿瘤细胞系中HLA I类分子在细胞表面的表达增加。特别是，早期对抗EGFR阻断抗体西妥昔单抗的研究表明，HLA I类分子在肿瘤中的表达增加与积极的临床反应相关。我们研究了另一种市售抗EGFR抗体尼妥珠单抗对肿瘤细胞系中HLA I类分子表达的影响。我们首次观察到，尼妥珠单抗可增加HLA I类分子的表达，其作用与主要抗原加工和呈递成分的mRNA水平协同增加有关。此外，使用7A7（一种针对小鼠EGFR的特异性替代抗体），我们获得的结果表明，EGFR靶向疗法诱导的MHC-I表达增加在抗肿瘤免疫反应中显示出更高的重要性。7A7疗法可诱导肿瘤MHC-I表达上调，用该抗体处理的肿瘤对CD8 T细胞介导的裂解更敏感。我们的结果首次证明了适应性免疫在尼妥珠单抗介导的抗肿瘤活性中的重要性。为了阐明这种机制在癌症患者中的相关性，应进行更多实验。尼妥珠单抗介导的这种新型免疫相关抗肿瘤机制为其与各种免疫治疗药物和癌症疫苗联合使用开辟了新的前景。
