Department of Hematology, Centre for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Denmark ; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Servicio de Analisis Clinicos e Inmunologia, UGC Laboratorio Clinico, Hospital Universitario Virgen de las Nieves, Granada, Spain ; Instituto de Investigacion Biosanitaria IBS, Granada, Spain ; Departamento de Bioquimica, Biologia Molecular e Inmunologia III, Universidad de Granada, Granada, Spain.
J Immunother Cancer. 2016 Apr 19;4:23. doi: 10.1186/s40425-016-0127-z. eCollection 2016.
Attention has recently focused on new cancer immunotherapy protocols aiming to activate T cell mediated anti-tumor responses. To this end, administration of antibodies that target inhibitory molecules regulating T-cell cytotoxicity has achieved impressive clinical responses, as has adoptive cell transfer (ACT) using expanded tumor infiltrating lymphocytes (TIL) or genetically modified cytotoxic T cells. However, despite clear clinical responses, only a fraction of patients respond to treatment and there is an urgent call for characterization of predictive biomarkers. CD8 positive T cells can infiltrate tumor tissues and destroy HLA class I positive tumor cells expressing the specific antigen. In fact, current progress in the field of cancer immune therapy is based on the capacity of T cells to kill cancer cells that present tumor antigen in the context on an HLA class I molecule. However, it is also well established that cancer cells are often characterized by loss or down regulation of HLA class I molecules, documented in a variety of human tumors. Consequently, immune therapy building on CD8 T cells will be futile in patients harboring HLA class-I negative or deficient cancer cells. It is therefore mandatory to explore if these important molecules for T cell cytotoxicity are expressed by cancer target cells. We have indications that different types of immunotherapy can modify the tumor microenvironment and up-regulate reduced HLA class I expression in cancer cells but only if the associated molecular mechanisms is reversible (soft). However, in case of structural (hard) aberrations causing HLA class I loss, tumor cells will not be able to recover HLA class I expression and as a consequence will escape T-cell lysis and continue to growth. Characterization of the molecular mechanism underlying the lack or downregulation of HLA class I expression, seems to be a crucial step predicting clinical responses to T cell mediated immunotherapy, and possibly aid the selection of strategies that could condition patients for response. Thus, characterization of HLA expression by cancer cells could therefore represent an important predictive marker for immunotherapy of cancer.
人们最近关注的焦点是新的癌症免疫治疗方案，旨在激活 T 细胞介导的抗肿瘤反应。为此，靶向调节 T 细胞细胞毒性的抑制分子的抗体的给药已取得令人印象深刻的临床反应，正如使用扩增的肿瘤浸润淋巴细胞（TIL）或基因修饰的细胞毒性 T 细胞进行过继细胞转移（ACT）一样。然而，尽管有明确的临床反应，但只有一部分患者对治疗有反应，因此迫切需要对预测生物标志物进行表征。CD8 阳性 T 细胞可以浸润肿瘤组织并破坏表达特定抗原的 HLA 类 I 阳性肿瘤细胞。事实上，癌症免疫治疗领域的当前进展基于 T 细胞杀伤在 HLA 类 I 分子背景下表达肿瘤抗原的癌细胞的能力。然而，众所周知，癌细胞通常表现为 HLA 类 I 分子的缺失或下调，在各种人类肿瘤中都有记录。因此，基于 CD8 T 细胞的免疫疗法在携带 HLA 类 I 阴性或缺陷的癌细胞的患者中是无效的。因此，必须探索这些对 T 细胞细胞毒性很重要的分子是否由癌症靶细胞表达。我们有迹象表明，不同类型的免疫疗法可以改变肿瘤微环境，并上调癌细胞中 HLA 类 I 的表达下调，但前提是相关的分子机制是可逆的（软性）。然而，在导致 HLA 类 I 缺失的结构（硬性）异常的情况下，肿瘤细胞将无法恢复 HLA 类 I 的表达，因此将逃避 T 细胞裂解并继续生长。阐明 HLA 类 I 表达缺失或下调的分子机制似乎是预测 T 细胞介导的免疫治疗临床反应的关键步骤，并可能有助于选择可能使患者对反应产生条件的策略。因此，癌细胞 HLA 表达的特征可能代表癌症免疫治疗的重要预测标志物。
