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Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
TIM-3 in endometrial carcinomas: an immunotherapeutic target expressed by mismatch repair-deficient and intact
Margaret Moore1, Kari L Ring2, Anne M Mills3
1University of Virginia School of Medicine, Charlottesville, VA, USA.
Abstract:
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.
Insights
Tumor cells and immune cells in endometrial cancer express TIM-3, a target for immunotherapy. High TIM-3 expression is linked to mismatch repair deficiency, MLH1-hypermethylation, MSH6 loss, and higher tumor grade, suggesting potential therapeutic roles.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) is an emerging immunotherapy target found on various cancer cells.
- Mismatch repair-deficient (MMRd) endometrial carcinomas show promise with checkpoint inhibitors due to high neoantigen loads.
- TIM-3 expression in endometrial cancer, particularly MMRd subtypes, remains largely uncharacterized.
Purpose of the Study:
- To investigate the expression patterns of TIM-3 in tumor cells and tumor-associated immune cells within different subtypes of endometrial carcinoma.
- To correlate TIM-3 expression with mismatch repair status (proficient vs. deficient), specific genetic alterations (MLH1 promoter hypermethylation, MSH6 loss), and tumor grade.
- To assess the potential of TIM-3 as a therapeutic target in endometrial cancer, including mismatch repair-intact cases.
Main Methods:
- Immunohistochemistry was employed to evaluate both tumoral and immune cell expression of TIM-3.
- The study analyzed 75 endometrial carcinoma samples categorized into three groups: MLH1 promoter hypermethylated, non-hypermethylated MMRd, and mismatch repair-intact (MMRp).
- Statistical analyses were performed to compare TIM-3 expression levels across these subgroups and correlate them with tumor grade and specific molecular features.
Main Results:
- All endometrial carcinoma cases exhibited at least focal immune cell TIM-3 staining, with moderate to robust expression more frequent in MMRd versus MMRp cases (66% vs. 12%, P=0.00002).
- Tumoral TIM-3 expression (≥1%) was observed in 77% of cases. The MLH1-hypermethylated subset showed significantly higher tumoral TIM-3 expression (>5%) compared to MMRp and non-methylated MMRd cancers (64% vs. 28% and 32%, P=0.02 and P=0.05, respectively).
- High tumoral TIM-3 expression was associated with MSH6 loss within the non-methylated MMRd group and with intermediate to high tumor grade across all subgroups (P=0.02 for both 1% and 5% cut-offs).
Conclusions:
- Tumoral TIM-3 expression is prevalent in endometrial cancers, with elevated levels in MLH1-hypermethylated, MSH6-deficient, and higher-grade tumors.
- Robust immune cell TIM-3 expression is significantly more common in MMRd endometrial cancers.
- These findings support TIM-3-targeting checkpoint inhibitors as a potential therapeutic strategy for a subset of endometrial cancers, including some MMRp tumors not currently considered for immunotherapy.
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