Dataset Information

Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers.

ABSTRACT:

Background

The aim of this study was to reveal the clinicopathological and molecular characteristics of microsatellite instability-high (MSI-H) colorectal cancers (CRCs) showing programmed death ligand-1 (PD-L1) positivity, which are good candidates for anti-PD-1/PD-L1 immunotherapy.

Methods

The PD-L1 expression status of 208 MSI-H CRCs was retrospectively analysed using immunohistochemistry. PD-L1 positivity in tumour cells (PD-L1+(T)) and PD-L1 positivity in immune cells (PD-L1+(I)) were separately evaluated.

Results

Programmed death ligand-1 positivity in tumour cells and PD-L1+(I) were observed in 26 (12.5%) and 62 (29.8%) MSI-H CRCs, respectively, and occasionally overlapped (n=12; 5.8%). Programmed death ligand-1 positivity tumours in MSI-H CRCs were significantly associated with older age, female sex, non-mucinous-type poor differentiation, infiltrating growth, tumour budding, advanced stage, CpG island methylator phenotype-high, MLH1 promoter methylation, and BRAF V600E mutations. However, PD-L1+(I) MSI-H CRCs were characterised by high-density tumour-infiltrating immune cells, including T cells and macrophages, and intense peritumoural lymphoid reactions. In patients with stage IV MSI-H CRCs who had undergone metastatectomy (n=4), the PD-L1 status of primary tumours was maintained in corresponding distant metastatic lesions.

Conclusions

In MSI-H CRCs, PD-L1+(T) and PD-L1+(I) are linked to a sporadic hypermethylated subtype and an immune cell-rich subtype, respectively. Potential differential therapeutic implications of PD-L1+(T) and PD-L1+(I) in CRCs should be further investigated.

SUBMITTER: Kim JH

PROVIDER: S-EPMC4985354 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers.

Kim Jung Ho JH Park Hye Eun HE Cho Nam-Yun NY Lee Hye Seung HS Kang Gyeong Hoon GH

British journal of cancer 20160712 4

<h4>Background</h4>The aim of this study was to reveal the clinicopathological and molecular characteristics of microsatellite instability-high (MSI-H) colorectal cancers (CRCs) showing programmed death ligand-1 (PD-L1) positivity, which are good candidates for anti-PD-1/PD-L1 immunotherapy.<h4>Methods</h4>The PD-L1 expression status of 208 MSI-H CRCs was retrospectively analysed using immunohistochemistry. PD-L1 positivity in tumour cells (PD-L1+(T)) and PD-L1 positivity in immune cells (PD-L1+ ...[more]

PMID: 27404452

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Project description:Preliminary clinical studies of anti-programmed cell death-1 (anti-PD-1) therapy in gastro-esophageal cancers have suggested promising single-agent activity. In patients who received prior treatment for advanced disease, pembrolizumab has been associated with a response rate of 20% in programmed cell death-1 ligand 1 (PD-L1)-positive tumors, and nivolumab with a response rate of 12% in unselected tumors. Both agents yielded a median duration of response lasting ~6-7 months. PD-L1 expression and microsatellite instability (MSI) have emerged as potential predictive markers for PD-1/PD-L1 blockade. PD-L1 expression in tumor cells and in immune cells within the tumor microenvironment has been detected in 14-24% and ~35% of patients with gastro-esophageal cancer, respectively. PD-L1 tumor cell expression appears to be more common in Epstein-Barr virus (EBV)-positive gastric cancers (GCs) and has been associated with an increased density of tumor-infiltrating lymphocytes (TIL). To date, data are too sparse to determine whether PD-L1 expression predicts efficacy of anti-PD-1 therapy in gastro-esophageal cancer, but data from other tumor types have not been consistent regarding its predictive value. MSI occurs in 10-20% of gastro-esophageal cancers and arises from deficient mismatch repair (MMR). MSI is highly correlated with non-synonymous mutation burden, as well as a dense accumulation of TILs. MSI has been associated with improved response to anti-PD-1 therapy in gastrointestinal cancers. Multiple studies are ongoing which examine therapeutic blockade of the PD-1/PD-L1 axis in unselected patients with gastro-esophageal cancer, as well as patients whose tumors express PD-L1 or exhibit MSI. These studies will clarify their activity in this disease and potentially can determine whether identify a strong predictive biomarker can be identified. Checkpoint inhibition is also being studied in combination with curative-intent chemo (radio) therapy and surgery.

Project description:We have performed bioinformatic approaches to identify the level of enrichment between gene expression profiles characterizing MSI tumors and gene changes induced in vitro by the PARP-1 inhibitor Phenanthridinone and others using the Connectivity Map tool. In a first step, we have anyzed the expression of 300 colorectal cancers from the MECC study and generated a gene expression signature by microsatellite status. The criteria followed for selection of probe sets and detailed lists to be submitted subsequently to the Connectivity Map have been published previously by us in Clinical Cancer Research in 2009. In a second step, once we observed that deficiency in MRE11 exist among MSI tumors, our interest was focused on assessing if the homologous recombination pathway showed evidence of deregulation in MSI tumors. Therefore, we examined the expression levels of those genes integrated in the KEGG pathway hsa03440 using the previously generated gene expression data set. The dataset generated from our samples included a total of 300 colorectal fresh frozen tumors collected from the MECC study and were analyzed in two batches. The first batch was hybridized to the Affymetrix U133A chip and the second one to U133 Plus 2.0 (Supplementary Table S3). The final list of probe sets defining gene expression of MSI-H compared to MSS tumors was selected based on the strength of multiplicity adjusted P-values (cut-off P-value of < 0.001) and ratio of mean expression values across the two groups (cut-off Fold-change >1.3 and <0.7). It contained 442 upregulated and 480 downregulated probe sets. Then, MSI-H tumors present with changes in gene expression related to the homologous recombination pathway. Therefore, we examined the expression levels of those genes integrated in the KEGG pathway hsa03440 using the same data set. A total of 14 genes out of 30 were significantly differentially expressed in MSI-H compared to MSS tumors (Multiplicity adjusted Benjamini-Hochberg P-value<0.05). MRE11 and RAD50 probe sets showed a lower expression in MSI-H tumors and simultaneously other probe sets such as PARP-1 were significantly upregulated, probably secondary to the deficiency in the MRN complex proteins. This data provides evidence of significant differential expression of the homologous recombination pathway in MSI tumors.

Dataset Information

Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers.

Background

Methods

Results

Conclusions

Publications

Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers.

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