University of Virginia School of Medicine (L.A.F.) University of Virginia Department of Obstetrics and Gynecology, Division of Gynecologic Oncology (K.L.R.) University of Virginia Department of Pathology (A.M.M.), Charlottesville, Virginia.
Int J Gynecol Pathol. 2020 May;39(3):203-212. doi: 10.1097/PGP.0000000000000608.
LAG-3 is an immunosuppressive checkpoint molecule expressed on T cells. One of its ligands, GAL-3, can promote the progression of malignancy and has been identified on tumor cells. Both LAG-3 and GAL-3 are the targets of emerging immunotherapies, but have not been well-studied in endometrial carcinomas. LAG-3, CD3, and GAL-3 immunohistochemistry was performed on 75 endometrial cancers (25 nonmethylated mismatch repair-deficient, 25 MLH1-hypermethylated mismatch repair-deficient, and 25 mismatch repair-intact). LAG-3 and CD3 lymphocytes were averaged per high-power field. Tumoral GAL-3 expression was semiquantitatively scored. Tumor-infiltrating lymphocyte expression of LAG-3 and CD3 were positively correlated (Spearman ρ=0.521, P<0.001) and greater in mismatch repair-deficient compared with mismatch repair-intact tumors (LAG-3: P<0.001; CD3: P<0.001). The majority (64%) of endometrial carcinomas demonstrated ≥1% tumoral GAL-3 expression, with higher rates in mismatch repair-deficient versus intact tumors at the ≥1% (80% vs. 32%, P<0.001) and the ≥5% thresholds (52% vs. 16%, P=0.003). At the ≥5% threshold, nonmethylated mismatch repair-deficient cancers were more likely than intact tumors carcinomas to express GAL-3 (60% vs. 4/25 16%, P=0.003). LAG-3 lymphocytes were positively correlated with GAL-3 expression in nonmethylated mismatch repair-deficient endometrial carcinomas only (Spearman ρ=0.461, P=0.020). LAG-3 tumor-associated lymphocytes and GAL-3 neoplastic cells are common in endometrial carcinomas, particularly in nonmethylated mismatch repair-deficient cancers. This supports a role for immunotherapies targeting LAG-3 and/or GAL-3 in a subset of endometrial carcinomas, potentially in concert with other checkpoint inhibitors.
LAG-3 是一种表达于 T 细胞上的免疫抑制检查点分子。其配体之一 GAL-3 可促进恶性肿瘤的进展，并已在肿瘤细胞上被识别。LAG-3 和 GAL-3 都是新兴免疫疗法的靶点，但在子宫内膜癌中研究甚少。对 75 例子宫内膜癌（25 例非甲基化错配修复缺陷型、25 例 MLH1 高甲基化错配修复缺陷型和 25 例错配修复完整型）进行了 LAG-3、CD3 和 GAL-3 免疫组化染色。每高倍视野计算 LAG-3 和 CD3 淋巴细胞的平均值。肿瘤内 GAL-3 的表达进行半定量评分。肿瘤浸润淋巴细胞的 LAG-3 和 CD3 表达呈正相关（Spearman ρ=0.521，P<0.001），且在错配修复缺陷型肿瘤中高于错配修复完整型肿瘤（LAG-3：P<0.001；CD3：P<0.001）。大多数（64%）子宫内膜癌表现出≥1%的肿瘤 GAL-3 表达，在错配修复缺陷型肿瘤中，≥1%（80%比 32%，P<0.001）和≥5%（52%比 16%，P=0.003）的阈值下，GAL-3 的表达率更高。在≥5%的阈值下，非甲基化错配修复缺陷型癌症比完整型肿瘤更有可能表达 GAL-3（60%比 25 例中的 4/25，16%，P=0.003）。仅在非甲基化错配修复缺陷型子宫内膜癌中，LAG-3 肿瘤相关淋巴细胞与 GAL-3 表达呈正相关（Spearman ρ=0.461，P=0.020）。LAG-3 肿瘤相关淋巴细胞和 GAL-3 肿瘤细胞在子宫内膜癌中很常见，特别是在非甲基化错配修复缺陷型癌症中。这支持了在子宫内膜癌的一个亚组中靶向 LAG-3 和/或 GAL-3 的免疫疗法的作用，可能与其他检查点抑制剂联合使用。
