Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Department of Gynecology and Obstetrics, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Mod Pathol. 2019 Apr;32(4):576-584. doi: 10.1038/s41379-018-0172-x. Epub 2018 Nov 6.
Mismatch repair-deficient endometrial cancers have a high somatic mutation burden, suggesting that patients with these tumors may benefit from immunotherapy. Elucidating the immune suppressive mechanisms of mismatch repair-deficient endometrial cancers is fundamental to developing future immune-based interventions. This study aimed to determine the immune cell populations associated with mismatch repair-deficient endometrial cancers, especially focusing on targetable regulatory pathways of the immune response. A total of 76 endometrial cancer hysterectomy specimens were evaluated for tumor-infiltrating immune cells by immunohistochemistry. Immune specific markers were used to evaluate each specimen for the number of CD8 + cytotoxic T lymphocytes, forkhead-box P3 (FoxP3) + regulatory T cells, CD68 + tumor-associated macrophages, as well as programmed death-1 (PD-1) + immune cells, and the percentage of programmed death ligand-1 (PD-L1) + immune cells. Mismatch repair-deficient tumors exhibited a significantly higher number of CD8 + cytotoxic T lymphocytes (p = 0.0006), FoxP3 + regulatory T cells (p = 0.0003), PD-1 + immune cells (p = 0.0069), and a higher percentage of PD-L1 + immune cells (p = 0.0007) occupying the tumor compared to mismatch repair-proficient endometrial cancers. There was no significant difference in CD68 + tumor-associated macrophages infiltration between the two groups. Endometrial cancers with tumor PD-L1 expression also showed significantly increased infiltration of CD8 + cytotoxic T lymphocytes (p = 0.0002), FoxP3 + regulatory T cells (p = 0.0003), PD-1 + immune cells (p < 0.0001), and PD-L1 + immune cells (p < 0.0001). Endometrial cancers showing mismatch repair-deficiency and PD-L1 expression in tumor cells exhibit a prominent T cell-inflamed phenotype. More importantly, the increased number of FoxP3 + regulatory T cells in mismatch repair-deficient endometrial cancers suggests that combination therapy by targeting both regulatory T cells and immune checkpoints may be warranted to improve clinical efficacy.
错配修复缺陷型子宫内膜癌具有较高的体细胞突变负担，这表明这些肿瘤患者可能受益于免疫治疗。阐明错配修复缺陷型子宫内膜癌的免疫抑制机制对于开发未来的免疫干预措施至关重要。本研究旨在确定与错配修复缺陷型子宫内膜癌相关的免疫细胞群体，特别是重点关注免疫反应的可靶向调节途径。共评估了 76 例子宫内膜癌子宫切除术标本中的肿瘤浸润免疫细胞，通过免疫组织化学染色。使用免疫特异性标志物评估每个标本的 CD8+细胞毒性 T 淋巴细胞、叉头框 P3（FoxP3）+调节性 T 细胞、CD68+肿瘤相关巨噬细胞以及程序性死亡-1（PD-1）+免疫细胞的数量，以及程序性死亡配体-1（PD-L1）+免疫细胞的百分比。错配修复缺陷型肿瘤表现出显著更高数量的 CD8+细胞毒性 T 淋巴细胞（p=0.0006）、FoxP3+调节性 T 细胞（p=0.0003）、PD-1+免疫细胞（p=0.0069）和更高百分比的 PD-L1+免疫细胞（p=0.0007）占据肿瘤与错配修复有效的子宫内膜癌相比。两组之间的 CD68+肿瘤相关巨噬细胞浸润没有显著差异。肿瘤 PD-L1 表达的子宫内膜癌也表现出显著增加的 CD8+细胞毒性 T 淋巴细胞浸润（p=0.0002）、FoxP3+调节性 T 细胞（p=0.0003）、PD-1+免疫细胞（p<0.0001）和 PD-L1+免疫细胞（p<0.0001）。显示肿瘤细胞中错配修复缺陷和 PD-L1 表达的子宫内膜癌表现出突出的 T 细胞浸润表型。更重要的是，错配修复缺陷型子宫内膜癌中 FoxP3+调节性 T 细胞数量的增加表明，针对调节性 T 细胞和免疫检查点的联合治疗可能是必要的，以提高临床疗效。
