Gynecological Oncology Programme, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Gynecological Cancer Translational Research Laboratory, INSERM U981, Gustave Roussy Institute, Villejuif, France.
J Immunother Cancer. 2024 Jul 1;12(7):e009143. doi: 10.1136/jitc-2024-009143.
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.
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，并非所有原发性耐药的反应和预测因素都缺乏。
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。
总的来说，NRs 表现出明显更低的 CD8，不存在终末分化的 T 细胞，缺乏成熟的三级淋巴样结构和树突状细胞，以及人类白细胞抗原 I 类的缺失。然而，没有任何单一的标志物可以有信心地预测 R 与 NR。聚类分析确定了四种免疫特征的组合，这些特征能够准确预测 ICI 反应，具有 92%的判别能力。最后，80%的 NRs 缺乏程序性死亡配体 1，但 60%表现出另一种可操作的免疫检查点（T 细胞免疫球蛋白和粘蛋白 3、吲哚胺 2,3-双加氧酶 1 或淋巴细胞激活基因 3）。
这些发现强调了免疫肿瘤微环境特征在识别 MMRd EC 患者和对 ICI 原发性耐药患者中的潜在作用，这些患者应该接受新型免疫治疗联合试验的检测。
