错配修复缺陷 (MMRd) 子宫内膜癌 (EC) 患者可以从免疫检查点抑制剂 (ICI) 中获益匪浅。然而，并非所有反应和原发耐药预测因子都缺乏。我们使用空间多重免疫分析和无监督层次聚类分析，比较了 MMRd EC ICI 反应者 (Rs) 和 ICI 无反应者 (NRs) 的免疫肿瘤微环境。总体而言，NRs表现出显着较低的 CD8、缺乏终末分化 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 类的缺失。然而，没有任何单一标记物可以可靠地预测 R 与 NR。聚类分析确定了四种免疫特征的组合，证明可以准确预测 ICI 反应，判别力为 92%。最后，80% 的 NR 缺乏程序性死亡配体 1，然而，60% 的 NR 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有蛋白 3、吲哚胺 2,3-双加氧酶 1 或淋巴细胞激活基因 3 的粘蛋白）。研究结果强调了免疫肿瘤微环境特征在识别 MMRd EC 和 ICI 原发性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。© 作者（或其雇主）2024。允许重复使用根据 CC BY-NC。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

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.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.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).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.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.