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

Xiao, Xue; Dong, Di; He, Weiqun; Li, Song; Wang, Qiao; Yue, Jun; Xie, Liang

doi:10.1016/j.ygyno.2018.02.009

Cited by 52 publications

(59 citation statements)

References 36 publications

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“…In a recent study of endometrial cancer, the presence of TILs (CD8 + ) and PD‐L1/PD‐1 expression were significantly higher in dMMR group compared to the MSS group, suggesting that immune checkpoint inhibitors could be effective in endometrial cancers with MSI . Supporting the hypothesis of immune evasion, dMMR ovarian carcinomas showed significantly increased CD3 + /CD8 + TILs and PD‐L1 expression in intratumoral immune cells compared to MMR‐proficient ovarian cancers . This is concordant with our results, which show higher PD‐L1 expression levels as well as increased CD3 + TILs and PD‐L1 + TILs in tumours with MLH1/PMS2 loss, with a statistically significant correlation between higher PD‐L1 score and MLH1/PMS2 loss.…”

Section: Discussionmentioning

confidence: 99%

“…PD‐1 modulates effector T cell activity by binding to one of its ligands, programmed cell death protein 1 ligand 1 (PD‐L1), which is expressed on a wide range of tumour cells. PD‐L1 overexpression has been associated with immune evasion in various tumour types, and provides a rationale for assessing tumour PD‐L1 expression in order to predict benefit from anti‐PD‐1/PD‐L1 immunotherapy, particularly in the setting of mismatch repair deficiency/microsatellite instability . Tumours with high mutational burden have been shown to be amenable to immune modulation .…”

Section: Introductionmentioning

confidence: 99%

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PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

et al. 2019

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Aims Neuroendocrine carcinoma, small cell type, of the uterine cervix (SmCC‐Cx) is a rare human papilloma virus (HPV) related tumour with limited therapeutic options. Merkel cell carcinoma, another virus‐associated neuroendocrine malignancy, has significant programmed death ligand 1 (PD‐L1) expression rates. PD‐L1 expression has been reported in other malignancies of the cervix. We aimed to determine the prevalence of PD‐L1 in the context of mismatch repair protein (MMR) and RB1 expression status in SmCC‐Cx. Methods and results Ten cases of SmCC‐Cx were tested by immunohistochemistry for expression of PD‐L1, MLH1, MSH2, MSH6, PMS2, RB1, CD3, CD20 and for HPV by in‐situ hybridisation (ISH). PD‐L1 expression was scored quantitatively (H‐score) in tumour cells and lymphocytes (tumoral/peritumoral). PD‐L1 positivity was seen in seven cases, focal in most (H‐score range 3–140). Three of nine cases showed MMR deficiency. PD‐L1 expression levels correlated with MMR expression status: all three MLH1/PMS2‐deficient cases had a ≥5% PD‐L1 staining and an H‐score ≥10 (P = 0.01). RB1 was lost in four of nine cases, all PD‐L1 positive, but this correlation was not statistically significant. Seven of nine tumours were positive for HPV‐ISH; two of these had MLH1/PMS2 loss. Of the two HPV‐ISH negative tumours, one had MLS1/PMS2 loss. Conclusions PD‐L1 expression, predominantly focal, is seen in 70% of SmCC‐Cx, while loss of MMR expression is seen in 33% of SmCC‐Cx in our cohort. PD‐L1 expression in more than 10% of tumour cells is seen in a subset of tumours in association with loss of MMR expression. These patients may be amenable to immune checkpoint inhibitor therapy as a promising alternative for this aggressive disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

et al. 2019

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“…This demonstrates that MMR‐deficient OC is more susceptible to immunotherapies based on PD‐1/PD‐L1 pathway antibodies. In conclusion, this type of treatment may emerge as effective in patients with early stages of endometrioid OC types .…”

Section: Perspectivesmentioning

confidence: 91%

Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment

Pawłowska

Suszczyk

Okła

et al. 2019

Clinical and Experimental Immunology

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Summary Immunotherapies based on anti‐programmed death 1/programmed death ligand 1 (PD‐1/PD‐L1) pathway inhibitors may turn out effective in ovarian cancer (OC) treatment. They can be used in combination with standard therapy and are especially promising in recurrent and platinum‐resistant OC. There is growing evidence that the mechanism of the PD‐1/PD‐L1 pathway can be specific for a particular histological cancer type. Interestingly, the data have shown that the PD‐1/PD‐L1 pathway blockade may be effective, especially in the endometrioid type of OC. It is important to identify the cause of anti‐tumor immune response suppression and exclude its other mechanisms in OC patients. It is also necessary to conduct subsequent studies to confirm in which OC cases the treatment is effective and how to select patients and combine drugs to improve patient survival.

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“…PFS is longer for MMR‐deficient women compared to MMR‐low and MMR‐proficient ovarian cancer ( P = .0046). They are also more likely to be diagnosed at an earlier stage ( P = .0041) . Ten‐year ovarian cancer‐specific survival has been found to be 80.6% in one series of MMR pathogenic variant carriers with ovarian cancer .…”

Section: Introductionmentioning

confidence: 99%

“…High mRNA expression of MSH6 , MLH1 , and PMS2 is associated with a significantly improved OS . It has been suggested these patients could be good candidates for checkpoint inhibitors …”

Section: Introductionmentioning

confidence: 99%

Epithelial ovarian cancer risk: A review of the current genetic landscape

et al. 2019

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Ovarian cancer is the fourth most common cause of cancer-related death in women in the developed world, and one of the most heritable cancers. One of the most significant risk factors for epithelial ovarian cancer (EOC) is a family history of breast and/or ovarian cancer. Combined risk factors can be used in models to stratify risk of EOC, and aid in decisions regarding risk-reduction strategies. Germline pathogenic variants in EOC susceptibility genes including those involved in homologous recombination and mismatch repair pathways are present in approximately 22% to 25% of EOC. These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) thought to explain an additional 6.4% of the familial risk of ovarian cancer, with 34 susceptibility loci identified to date. However, an unknown proportion of the genetic component of EOC risk remains unexplained.This review comprises an overview of individual genes and SNPs suspected to contribute to risk of EOC, and discusses use of a polygenic risk score to predict individual cancer risk more accurately. K E Y W O R D SBRCA, genetic risk, homologous recombination, mismatch repair, ovarian cancer, polygenic risk score, SNPs

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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

Cited by 52 publications

References 36 publications

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment

Epithelial ovarian cancer risk: A review of the current genetic landscape

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