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Removal of N-Linked Glycosylation Enhances PD-L1 Detection in Colon Cancer: Validation Research Based on Immunohistochemistry Analysis.

ABSTRACT: In recent years, immunotherapies have emerged as effective therapeutic strategies for treating human cancers. However, accumulating evidence has revealed an inconsistency between the response to immune checkpoint inhibitors and programmed death ligand 1 (PD-L1) expression status detected by immunohistochemistry staining. Recent research has revealed that the removal of N-Linked glycosylation significantly enhanced PD-L1 detection, resulting in both more accurate PD-L1 quantification and clinical outcome prediction. In the present study, we evaluated natural and deglycosylated PD-L1 expression in colon cancer using the PD-L1 28-8 antibody. The results of the present study validated the hypothesis that PD-L1 had a higher expression in colon cancer tissues compared with normal tissues. Additionally, colon tumors with defective mismatch repair tended to express higher PD-L1 than those without. Most importantly, the results of the present study indicated that the removal of N-linked glycosylation remarkably enhanced PD-L1 detection. Moreover, the PD-L1 signal intensity of samples with a low natural PD-L1 signal was enhanced more remarkably than that of samples with high signal intensity. Overall, our research provides an improved strategy for patient stratification for anti-PD-1/PD-L1 therapy, which deepens the clinical significance of this established strategy for treatment of colon cancer.

SUBMITTER: Xu J

PROVIDER: S-EPMC8173990 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFor non-small cell lung cancer (NSCLC), treatment with pembrolizumab is limited to patients with tumours expressing PD-L1 assessed by immunohistochemistry (IHC) using the PD-L1 IHC 22C3 pharmDx (Dako, Inc.) companion diagnostic test, on the Dako Autostainer Link 48 (ASL48) platform. Optimised protocols are urgently needed for use of the 22C3 antibody concentrate to test PD-L1 expression on more widely available IHC autostainers.MethodsWe evaluated PD-L1 expression using the 22C3 antibody concentrate in the three main commercially available autostainers Dako ASL48, BenchMark ULTRA (Ventana Medical Systems, Inc.), and Bond-III (Leica Biosystems) and compared the staining results with the PD-L1 IHC 22C3 pharmDx kit on the Dako ASL48 platform. Several technical conditions for laboratory-developed tests (LDTs) were evaluated in tonsil specimens and a training set of three NSCLC samples. Optimised protocols were then validated in 120 NSCLC specimens.ResultsOptimised protocols were obtained on both the VENTANA BenchMark ULTRA and Dako ASL48 platforms. Significant expression of PD-L1 was obtained on tissue controls with the Leica Bond-III autostainer when high concentrations of the 22C3 antibody were used. It therefore was not tested on the 120 NSCLC specimens. An almost 100% concordance rate for dichotomized tumour proportion score (TPS) results was observed between TPS ratings using the 22C3 antibody concentrate on the Dako ASL48 and VENTANA BenchMark ULTRA platforms relative to the PD-L1 IHC 22C3 pharmDx kit on the Dako ASL48 platform. Interpathologist agreement was high on both LDTs and the PD-L1 IHC 22C3 pharmDx kit on the Dako ASL48 platform.ConclusionAvailability of standardized protocols for determining PD-L1 expression using the 22C3 antibody concentrate on the widely available Dako ASL48 and VENTANA BenchMark ULTRA IHC platforms will expand the number of laboratories able to determine eligibility of patients with NSCLC for treatment with pembrolizumab in a reliable and concordant manner.

Project description:Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using "PD-L1" as a search term for 01/01/2015 to 31/08/2018, with limitations "English" and "human". 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.

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Removal of N-Linked Glycosylation Enhances PD-L1 Detection in Colon Cancer: Validation Research Based on Immunohistochemistry Analysis.

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