The degree of microsatellite instability predicts response to PD-1 blockade immunotherapy in mismatch repair-deficient/microsatellite instability-high colorectal cancers

Wang, Qiaoxuan; Qu, Chunhua; Gao, Yuanhong; Ding, Pei-Rong; Yun, Jing‐Ping; Xie, Dan; Cai, Mengli

doi:10.1186/s40164-020-00193-z

Cited by 18 publications

(12 citation statements)

References 6 publications

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“…DNA mismatch repair (MMR), which is vital for the maintenance of genomic stability, has been identified to play critical roles in the pathogenesis of AML [ 151 ]. Recent findings have suggested that a high degree of microsatellite instability can predict patient response to PD-1 blocker in colorectal cancer [ 152 ]. IFN-γ is secreted by activated CD8 + T cells to inhibit tumor cell proliferation, while it also upregulates PD-L1 on these cells [ 153 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Yang

Zhang

et al. 2022

Exp Hematol Oncol

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Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases arising from the bone marrow (BM), and approximately 30% of MDS eventually progress to AML, associated with increasingly aggressive neoplastic hematopoietic clones and poor survival. Dysregulated immune microenvironment has been recognized as a key pathogenic driver of MDS and AML, causing high rate of intramedullary apoptosis in lower-risk MDS to immunosuppression in higher-risk MDS and AML. Immune checkpoint molecules, including programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), play important roles in oncogenesis by maintaining an immunosuppressive tumor microenvironment. Recently, both molecules have been examined in MDS and AML. Abnormal inflammatory signaling, genetic and/or epigenetic alterations, interactions between cells, and treatment of patients all have been involved in dysregulating PD-1/PD-L1 signaling in these two diseases. Furthermore, with the PD-1/PD-L1 pathway activated in immune microenvironment, the milieu of BM shift to immunosuppressive, contributing to a clonal evolution of blasts. Nevertheless, numerous preclinical studies have suggested a potential response of patients to PD-1/PD-L1 blocker. Current clinical trials employing these drugs in MDS and AML have reported mixed clinical responses. In this paper, we focus on the recent preclinical advances of the PD-1/PD-L1 signaling in MDS and AML, and available and ongoing outcomes of PD-1/PD-L1 inhibitor in patients. We also discuss the novel PD-1/PD-L1 blocker-based immunotherapeutic strategies and challenges, including identifying reliable biomarkers, determining settings, and exploring optimal combination therapies.

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Section: Future Perspectivesmentioning

confidence: 99%

Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Yang

Zhang

et al. 2022

Exp Hematol Oncol

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“…When the association between the two qualitative variables was evaluated, there was a statistically significant relationship based on the results of a chi-squared test. This relationship shows how cases with a loss of expression of the repair genes present a greater response, primarily at the expense of patients with partial responses [ 23 ]. These observations were not influenced by other factors such as age, sex, or histological subtype.…”

Section: Discussionmentioning

confidence: 99%

Influence of DNA Mismatch Repair (MMR) System in Survival and Response to Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC): Retrospective Analysis

et al. 2022

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Mutations in the mismatch repair (MMR) system predict the response to immune checkpoint inhibitors (ICIs) like colon or gastric cancer. However, the MMR system’s involvement in non-small cell lung cancer (NSCLC) remains unknown. Addressing this issue will improve clinical guidelines in the case of mutations in the main genes of the MMR system (MLH1, MSH2, MSH6, and PMS2). This work retrospectively assessed the role that these gene mutations play in the response to and survival of ICIs in NSCLC. Patients with NSCLC treated with nivolumab as the second-line treatment in the University Hospital of Salamanca were enrolled in this study. Survival and response analyses were performed according to groups of MMR system gene expression (MMR expression present or deficiency) and other subgroups, such as toxicity. There was a statistically significant relationship between the best response obtained and the expression of the MMR system (p = 0.045). The presence of toxicity grade ≥ 3 was associated with the deficiency expression of MMR (dMMR/MSI-H) group (p = 0.022; odds ratio = 10.167, 95% confidence interval (CI) 1.669–61.919). A trend towards greater survival and response to ICIs was observed in NSCLC and dMMR. Assessing the genes in the MMR system involved in NSCLC is key to obtaining personalized immunotherapy treatments.

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“…In the present study, the microsatellite instability status was correlated with the tumour PD-L1 expression score in pre-neoCRT biopsies. The possible mechanism resulted from the increased tumors immunogenicity and lymphocytic infltration [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Programmed death-ligand 1 and mammalian target of rapamycin signaling pathway in locally advanced rectal cancer

et al. 2022

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Purpose To evaluate the role of programmed death-ligand 1 (PD-L1) and mammalian target of rapamycin (mTOR) signaling pathway in locally advanced rectal cancer (LARC). Methods Between February 2012 and February 2018, 103 patients with LARC treated by neoadjuvant chemoradiotherapy (neoCRT) and total mesorectal excision (TME) were included. PD-L1, mTOR and p-mTOR of pair-matched pre-neoCRT biopsies and post-neoCRT surgical tissue were evaluated by immunohistochemistry. Results The mean combined positive score (CPS), tumor proportion score (TPS) and immune cell score (IC) of pre-neoCRT were 2.24 (0–70), 1.87 (0–70) and 0.67 (0–10), respectively. The mean CPS, TPS and IC of post-neoCRT were 2.19 (0–80), 1.38 (0–80) and 1.60 (0–20), respectively. Significant difference was observed in terms of IC between pre-neoCRT and post-neoCRT (p = 0.010). The 5-year disease-free survival (DFS) rate of the whole group was 62.4%. Multivariate analysis by Cox model indicated that pre-neoCRT TPS [hazard ratio (HR) 1.052, 95% confidence interval (CI) 1.020–1.086, p = 0.001] and post-neoCRT CPS (HR 0.733, 95% CI 0.555–0.967, p = 0.028) were associated with DFS. In the 89 patients without pathological complete response, p-mTOR and IC were upregulated after neoCRT. Conclusions For patients with LARC treated by neoCRT and TME, p-mTOR and IC were upregulated after neoCRT. Pre-neoCRT TPS and post-neoCRT CPS were independent prognostic predictors of DFS.

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The degree of microsatellite instability predicts response to PD-1 blockade immunotherapy in mismatch repair-deficient/microsatellite instability-high colorectal cancers

Cited by 18 publications

References 6 publications

Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Influence of DNA Mismatch Repair (MMR) System in Survival and Response to Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC): Retrospective Analysis

Programmed death-ligand 1 and mammalian target of rapamycin signaling pathway in locally advanced rectal cancer

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