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Mismatch repair deficiency is associated with MSI phenotype, increased tumor-infiltrating lymphocytes and PD-L1 expression in immune cells in ovarian cancer

  • Xue Xiao
    Correspondence
    Corresponding authors.
    Affiliations
    Individualized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China
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  • Dandan Dong
    Affiliations
    Department of Pathology, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China
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  • Wenjing He
    Affiliations
    Department of Gynecology and Obstetrics, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China
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  • Linhong Song
    Affiliations
    Department of Pathology, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China
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  • Qiao Wang
    Affiliations
    Department of Gynecology and Obstetrics, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China
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  • Jun Yue
    Affiliations
    Department of Gynecology and Obstetrics, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China
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  • Lan Xie
    Correspondence
    Corresponding authors.
    Affiliations
    Department of Gynecology and Obstetrics, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China
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Published:February 26, 2018DOI:https://doi.org/10.1016/j.ygyno.2018.02.009

      Highlights

      • MMR deficiency is generally presented at early-stage OCs with better prognosis.
      • Complete loss of MLH1 and MSH2 is strongly associated with MSI-H phenotype.
      • MMR deficient OCs show an increase of TILs and PD-L1+ intratumoral immune cells.

      Abstract

      Objective

      The role of mismatch repair (MMR) deficiency in ovarian cancer (OC) pathogenesis and its association with other clinicopathologic features, such as microsatellite instability (MSI) and expression of checkpoint proteins, remain largely elusive.

      Methods

      We performed Immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 on full-section slides from 419 OCs to assess the MMR status. The clinical relevance of MMR deficiency was analyzed in combination with clinical data. The MSI status (by MSI assay) and expression of CD3, CD8, PD-1 and PD-L1 (by IHC) were compared in OCs with different MMR status.

      Results

      We found that 2.6% OCs were MMR-negative, 4.3% OCs were MMR-low, and 63.6% of MMR-negative OCs were of endometrioid subtype. A significantly higher proportion of MMR-negative OCs were diagnosed at stage I or II compared to MMR-proficient OCs (p = 0.0041). MSI was observed in all tested MMR-negative OCs, 14.3% of tested MMR-low OCs and 3.2% of tested MMR-proficient OCs. In addition, MMR-negative OCs had better progression free survival compared to MMR-proficient and MMR-low OCs (p = 0.0046). Furthermore, the majority of OCs were PD-1-positive in intratumoral lymphocytes regardless of MMR status; while MMR-negative OCs exhibited significantly increased CD3+ and CD8+ tumor-infiltrating lymphocytes, and PD-L1+ intratumoral immune cells compared to MMR-proficient OCs.

      Conclusion

      Our data suggests that MMR deficient OC is a unique molecular subgroup, characterized by early stage of diagnosis, MSI phenotype, and increased tumor-infiltrating lymphocytes. These patients may be good candidates for anti-PD-1/PD-L1 therapy.

      Keywords

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