Rousset-Rouviere Sandrine, Rochigneux Philippe, Chrétien Anne-Sophie, Fattori Stéphane, Gorvel Laurent, Provansal Magali, Lambaudie Eric, Olive Daniel, Sabatier Renaud
Immunomonitoring Department, Institut Paoli-Calmettes, 13009 Marseille, France.
Department of Surgical Oncology, Institut Paoli-Calmettes, 13009 Marseille, France.
Biomedicines. 2021 Jun 2;9(6):632. doi: 10.3390/biomedicines9060632.
Endometrial cancer (EC) can easily be cured when diagnosed at an early stage. However, advanced and metastatic EC is a common disease, affecting more than 15,000 patients per year in the United Sates. Only limited treatment options were available until recently, with a taxane-platinum combination as the gold standard in first-line setting and no efficient second-line chemotherapy or hormone therapy. EC can be split into four molecular subtypes, including hypermutated cases with POLE mutations and 25-30% harboring a microsatellite instability (MSI) phenotype with mismatch repair deficiency (dMMR). These tumors display a high load of frameshift mutations, leading to increased expression of neoantigens that can be targeted by the immune system, including (but not limited) to T-cell response. Recent data have demonstrated this impact of programmed death 1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors on chemo-resistant metastatic EC. The uncontrolled KEYNOTE-158 and GARNET trials have shown high response rates with pembrolizumab and dostarlimab in chemoresistant MSI-high tumors. Most responders experiment long responses that last more than one year. Similar, encouraging results were obtained for MMR proficient (MMRp) cases treated with a combination of pembrolizumab and the angiogenesis inhibitor lenvatinib. Approvals have, thus, been obtained or are underway for EC with immune checkpoint inhibitors (ICI) used as monotherapy, and in combination with antiangiogenic agents. Combinations with other targeted therapies are under evaluation and randomized studies are ongoing to explore the impact of ICI-chemotherapy triplets in first-line setting. We summarize in this review the current knowledge of the immune environment of EC, both for MMRd and MMRp tumors. We also detail the main clinical data regarding PD-1/PD-L1 inhibitors and discuss the next steps of development for immunotherapy, including various ICI-based combinations planned to limit resistance to immunotherapy.
子宫内膜癌（EC）在早期诊断时很容易治愈。然而，晚期和转移性EC是一种常见疾病，在美国每年影响超过15000名患者。直到最近，可用的治疗选择都很有限，紫杉烷-铂联合方案是一线治疗的金标准，且没有有效的二线化疗或激素治疗。EC可分为四种分子亚型，包括具有POLE突变的高突变病例以及25%-30%携带微卫星不稳定（MSI）表型且错配修复缺陷（dMMR）的病例。这些肿瘤显示出高负荷的移码突变，导致新抗原表达增加，而新抗原可被免疫系统靶向，包括（但不限于）T细胞反应。最近的数据表明程序性死亡1和程序性死亡配体1（PD-1/PD-L1）抑制剂对化疗耐药的转移性EC有影响。未设对照的KEYNOTE-158和GARNET试验显示，帕博利珠单抗和多斯塔利单抗在化疗耐药的MSI高肿瘤中具有高缓解率。大多数缓解者有持续超过一年的长期缓解。对于接受帕博利珠单抗和血管生成抑制剂乐伐替尼联合治疗的错配修复功能正常（MMRp）病例，也获得了类似的鼓舞人心的结果。因此，免疫检查点抑制剂（ICI）作为单一疗法以及与抗血管生成药物联合使用治疗EC已获批或正在审批中。与其他靶向疗法的联合正在评估中，随机研究也在进行，以探索ICI-化疗三联疗法在一线治疗中的影响。在本综述中，我们总结了目前关于MMRd和MMRp肿瘤的EC免疫环境的知识。我们还详细介绍了关于PD-1/PD-L1抑制剂的主要临床数据，并讨论了免疫治疗的下一步发展，包括计划用于限制免疫治疗耐药性的各种基于ICI的联合方案。
