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Advances in Immunotherapy for Endometrial Cancer: Insights into MMR Status and Tumor Microenvironment
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Oncologic Pathology Group, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida (UdL), Av. Rovira Roure 80, 25198 Lleida, Spain
2
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
3
Developmental and Oncogenic Signaling, Biomedical Research Institute of Lleida (IRBLleida), University of Lleida (UdL), Av. Rovira Roure 80, 25198 Lleida, Spain
*
Authors to whom correspondence should be addressed.
Cancers 2024, 16(23), 3918; https://doi.org/10.3390/cancers16233918
Submission received: 30 October 2024
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Revised: 18 November 2024
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Accepted: 19 November 2024
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Published: 22 November 2024
(This article belongs to the Special Issue Drug Utilization, Safety and Effectiveness of Anti-Cancer Drugs for Solid Tumors: A Focus on Special Populations)
Simple Summary
Endometrial cancer (EC), while generally curable in early stages, poses significant challenges when it recurs or advances. Recent advancements in immunotherapy, specifically immune checkpoint inhibitors, have provided a promising therapeutic option for such cases, especially with FDA-approved drugs like pembrolizumab, durvalumab, and dostarlimab. The molecular classification of EC, particularly mismatch repair deficiency, has proven essential in identifying tumors that are likely to respond to immune checkpoint inhibitors, owing to their increased tumor mutational burden and higher PD-L1 expression. However, mismatch repair (MMR) status alone is insufficient to predict immune responses as treatment outcomes are also substantially influenced by tumor microenvironment composition, immune infiltration, and inter-individual variability. Emerging cell therapies like Chimeric Antigen Receptor (CAR) T cells and tumor-infiltrating lymphocytes offer hope for addressing non-immunogenic tumors, overcoming immune evasion mechanisms that limit natural immune responses.
Abstract
Endometrial cancer is one of the most common gynecological malignancies, and while early-stage cases are highly treatable, recurrent or advanced EC remains challenging to manage. Immunotherapy, particularly immune checkpoint inhibitors, has revolutionized treatment approaches in oncology, and its application in EC has shown promising results. Key to immunotherapy efficacy in EC is the tumor’s mismatch repair status, with MMR-deficient tumors demonstrating a higher tumor mutational burden and increased PD-L1 expression, making them more susceptible to immune checkpoint inhibitors (ICIs) such as pembrolizumab, durvalumab, and dostarlimab. However, not all mismatch repair-deficient (MMRd) tumors respond to ICIs, particularly those with a “cold” tumor microenvironment (TME) characterized by poor immune infiltration. In contrast, some MMR-proficient tumors with a “hot” TME respond well to ICIs, underscoring the complex interplay between MMR status, tumor mutational burden (TMB), and TME. To overcome resistance in cold tumors, novel therapies, including Chimeric Antigen Receptor (CAR) T cells and tumor-infiltrating lymphocytes are being explored, offering targeted immune-based strategies to enhance treatment efficacy. This review discusses the current understanding of immunotherapy in EC, emphasizing the prognostic and therapeutic implications of MMR status, TME composition, and emerging cell-based therapies.
