LAG-3 and GAL-3 in Endometrial Carcinoma: Emerging Candidates for Immunotherapy

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.