PDF(Pubmed)
Abstract：
BACKGROUND: Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking.
METHODS: We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis.
RESULTS: Overall, NRs exhibited drastically lower CD8+, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3).
CONCLUSIONS: These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.
METHODS: We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis.
RESULTS: Overall, NRs exhibited drastically lower CD8+, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3).
CONCLUSIONS: These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.
摘要：
背景：错配修复缺陷（MMRd）子宫内膜癌（EC）的患者可以从免疫检查点抑制剂（ICI）中获得巨大的益处。然而，并不是所有的反应和预测的主要抗性缺乏。
方法：我们比较了MMRdECICI应答者（Rs）和ICI非应答者（NRs）的免疫肿瘤微环境，使用空间多重免疫谱分析和无监督层次聚类分析。
结果：总体而言，NRs表现出显著降低的CD8+，不存在终末分化的T细胞，缺乏成熟的三级淋巴结构和树突状细胞，以及人类白细胞抗原I类的丢失。然而，没有一个单一的标志物可以可靠地预测R和NR。聚类分析确定了四个免疫特征的组合，证明了准确预测ICI反应，具有92%的鉴别力。最后,80%的NRs缺乏程序性死亡配体1，然而，60％表现出另一个可操作的免疫检查点（T细胞免疫球蛋白和含蛋白3的粘蛋白，吲哚胺2,3-双加氧酶1或淋巴细胞激活基因3）。
结论：这些发现强调了免疫肿瘤微环境特征在识别MMRdEC和ICI主要耐药患者方面的潜力，这些患者应面向测试新型免疫治疗组合的试验。
方法：我们比较了MMRdECICI应答者（Rs）和ICI非应答者（NRs）的免疫肿瘤微环境，使用空间多重免疫谱分析和无监督层次聚类分析。
结果：总体而言，NRs表现出显著降低的CD8+，不存在终末分化的T细胞，缺乏成熟的三级淋巴结构和树突状细胞，以及人类白细胞抗原I类的丢失。然而，没有一个单一的标志物可以可靠地预测R和NR。聚类分析确定了四个免疫特征的组合，证明了准确预测ICI反应，具有92%的鉴别力。最后,80%的NRs缺乏程序性死亡配体1，然而，60％表现出另一个可操作的免疫检查点（T细胞免疫球蛋白和含蛋白3的粘蛋白，吲哚胺2,3-双加氧酶1或淋巴细胞激活基因3）。
结论：这些发现强调了免疫肿瘤微环境特征在识别MMRdEC和ICI主要耐药患者方面的潜力，这些患者应面向测试新型免疫治疗组合的试验。
