Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; email:
Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
Annu Rev Med. 2018 Jan 29;69:333-347. doi: 10.1146/annurev-med-060116-022926. Epub 2017 Nov 3.
Molecularly targeted therapy and immunotherapy have dramatically changed the landscape of available treatment options for patients with advanced cancer. Improved understanding of the molecular and genomic features of cancers over the last decade has led to the development of successful targeted therapies and the field of precision cancer medicine. As a result of these advances, patients whose tumors harbor select molecular alterations are eligible for treatment with targeted therapies active against the unique molecular aberration. Concurrently, advances in tumor immunology have led to the development of immunomodulatory antibodies targeting T cell coinhibitory receptors CTLA-4 and PD-1 (programmed death-1) that have shown activity in several cancer histologies, reinvigorating antitumor immune responses in a subset of patients. These immunomodulatory antibodies offer the promise of durable disease control. However, discrete genomic determinants of response to cancer immunotherapy, unlike molecularly targeted therapies, have remained elusive, and robust biomarkers are lacking. Recent advances in tumor profiling have begun to identify novel genomic features that may influence response and resistance to cancer immunotherapy, including tumor mutational burden (e.g., microsatellite instability), copy-number alterations, and specific somatic alterations that influence immune recognition and response. Further investigation into the molecular and genomic features of response and resistance to cancer immunotherapy will be needed. We review the recent advances in understanding the molecular and genomic determinants of response to cancer immunotherapy, with an emphasis on immune checkpoint inhibitors.
分子靶向治疗和免疫治疗极大地改变了晚期癌症患者的治疗选择。过去十年中对癌症分子和基因组特征的深入了解，导致了成功的靶向治疗和精准癌症医学领域的发展。由于这些进展，其肿瘤具有特定分子改变的患者有资格接受针对独特分子异常的靶向治疗。同时，肿瘤免疫学的进步导致了针对 T 细胞共抑制受体 CTLA-4 和 PD-1（程序性死亡受体 1）的免疫调节抗体的开发，这些抗体在几种癌症组织学中具有活性，在一部分患者中重新激活了抗肿瘤免疫反应。这些免疫调节抗体有望实现持久的疾病控制。然而，与分子靶向治疗不同，癌症免疫治疗反应的离散基因组决定因素仍然难以捉摸，并且缺乏强大的生物标志物。最近肿瘤分析方面的进展开始确定可能影响癌症免疫治疗反应和耐药性的新型基因组特征，包括肿瘤突变负担（例如微卫星不稳定性）、拷贝数改变以及影响免疫识别和反应的特定体细胞改变。需要进一步研究癌症免疫治疗反应和耐药性的分子和基因组特征。我们回顾了对癌症免疫治疗反应的分子和基因组决定因素的最新理解进展，重点介绍了免疫检查点抑制剂。
