Karpanen Terhi, Olweus Johanna
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, and K.G. Jebsen Center for Cancer Immunotherapy, University of Oslo, Oslo, Norway.
Front Immunol. 2017 Dec 11;8:1718. doi: 10.3389/fimmu.2017.01718. eCollection 2017.
T cells can recognize peptides encoded by mutated genes, but analysis of tumor-infiltrating lymphocytes suggests that very few neoantigens spontaneously elicit T-cell responses. This may be an important reason why immune checkpoint inhibitors are mainly effective in tumors with a high mutational burden. Reasons for clinically insufficient responses to neoantigens might be inefficient priming, inhibition, or deletion of the cognate T cells. Responses can be dramatically improved by cancer immunotherapy such as checkpoint inhibition, but often with temporary effects. By contrast, T cells from human leukocyte antigen (HLA)-matched donors can cure diseases such as chronic myeloid leukemia. The therapeutic effect is mediated by donor T cells recognizing polymorphic peptides for which the donor and patient are disparate, presented on self-HLA. Donor T-cell repertoires are unbiased by the immunosuppressive environment of the tumor. A recent study demonstrated that T cells from healthy individuals are able to respond to neoantigens that are ignored by tumor-infiltrating T cells of melanoma patients. In this review, we discuss possible reasons why neoantigens escape host T cells and how these limitations may be overcome by utilization of donor-derived T-cell repertoires to facilitate rational design of neoantigen-targeted immunotherapy.
T细胞能够识别由突变基因编码的肽段，但对肿瘤浸润淋巴细胞的分析表明，极少有新抗原能自发引发T细胞反应。这可能是免疫检查点抑制剂主要对高突变负荷肿瘤有效的一个重要原因。临床上对新抗原反应不足的原因可能是同源T细胞的启动、抑制或缺失效率低下。通过诸如检查点抑制等癌症免疫疗法，反应可以得到显著改善，但往往只是暂时的效果。相比之下，来自人类白细胞抗原（HLA）匹配供体的T细胞可以治愈慢性髓系白血病等疾病。治疗效果是由供体T细胞介导的，这些T细胞识别供体和患者不同的多态性肽段，并呈递在自身HLA上。供体T细胞库不受肿瘤免疫抑制环境的影响。最近一项研究表明，健康个体的T细胞能够对黑色素瘤患者肿瘤浸润T细胞忽略的新抗原产生反应。在这篇综述中，我们讨论了新抗原逃避宿主T细胞的可能原因，以及如何通过利用供体来源的T细胞库来克服这些限制，以促进新抗原靶向免疫疗法的合理设计。
