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The checkpoint molecule TIM-3 is a target for emerging immunotherapies and has been identified on a variety of malignancies. Mismatch repair-deficient endometrial carcinomas have demonstrated durable responses to other checkpoint inhibitors due to high neoantigen loads and robust tumor-associated immune responses. However, little is known about TIM-3 expression in this tumor type. Tumor-associated immune and tumoral expression of TIM-3 were evaluated by immunohistochemistry on 75 endometrial carcinomas [25 MLH1 promoter hypermethylated (MLH1-hypermethylated), 25 non-hypermethylated mismatch repair-deficient, and 25 mismatch repair-intact]. All cases showed at least focal immune staining, but moderate and robust immune cell expression were more often observed in mismatch repair-deficient vs intact cases [66 vs 12%, P = 0.00002]. While the majority (77%) of endometrial cancers showed ≥1% tumoral TIM-3 expression, the MLH1-hypermethylated subset was more likely to demonstrate >5% tumoral staining when compared to both mismatch repair-intact and non-methylated mismatch repair-deficient cancers [64 vs. 28% and 32%, respectively; P = 0.02 and P = 0.05]. Within the non-methylated mismatch repair-deficient subset, high-level expression was most often associated with MSH6 loss. Across mismatch repair subgroups, tumoral TIM-3 expression was more common among intermediate and high-grade vs. low-grade tumors using both the 1% (P = 0.02) and 5% expression cut-offs (P = 0.02). In conclusion, tumoral TIM-3 expression is common in both mismatch repair-intact and deficient endometrial cancers, with particularly high levels of expression identified in the setting of MLH1-hypermethylation, MSH6 loss, and intermediate to high histologic grade. Although focal immune cell expression was seen in all tumors, robust expression was significantly more common in the context of mismatch repair deficiency. These data support a potential role for checkpoint inhibitors targeting TIM-3 in a subset of endometrial cancers, including some mismatch repair-intact tumors which are not currently considered immunotherapy candidates.
This article was published in the following journal.
Name: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
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Eukaryotic homolog of the bacterial MutL DNA MISMATCH REPAIR protein. It heterodimerizes with MISMATCH REPAIR ENDONUCLEASE PMS2 to form MutL alpha, which is recruited to DNA mismatch sites by the MUTS DNA MISMATCH-BINDING PROTEIN. Mutations in the human MLH1 gene are associated with COLORECTAL NEOPLASMS, HEREDITARY NONPOLYPOSIS.
A MutL protein and component of the DNA MISMATCH REPAIR system. Its ENDONUCLEASE activity introduces SINGLE-STRAND DNA BREAKS which create entry points for EXO1 exonuclease to remove the strand containing the mismatch. It may also function in DNA DAMAGE signaling.
DNA repair proteins that include the bacterial MutL protein and its eukaryotic homologs. They consist of a conserved N-terminal region with weak ATPase activity, an endonuclease motif, and a C-terminal domain that forms MutL homodimers or heterodimers between MLH1 and the PMS1, MISMATCH REPAIR ENDONUCLEASE PMS2; or MLH3 proteins. These complexes function in DNA repair pathways, primarily DNA MISMATCH REPAIR, where MutL/MLH1 and the MUTS DNA MISMATCH-BINDING PROTEIN are targeted to damaged DNA.
DNA repair proteins that include the bacterial MutS DNA mismatch-binding protein and its eukaryotic homologs that function in DNA MISMATCH REPAIR and recombination of DNA during MEIOSIS. MutS has a conserved mismatch recognition domain characterized by GxFxE, or similar AMINO ACID MOTIFS that also occur in eukaryotic homologs such as MSH1, MSH6, and MSH8. All MutS proteins also contain a highly-conserved ATP-binding domain and most have weak ATPase activity.
A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the BASE PAIR MISMATCH and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. (from Oxford Dictionary of Biochemistry and Molecular Biology, 2001)