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  • Immunohistochemistry IHC is widely used as a companion

    2019-08-26

    Immunohistochemistry (IHC) is widely used as a companion/complemental PD-L1 assay for the use of PD1/PDL1 inhibitors [3,[5], [6], [7]]. However, there are several problems with the assessment of PD-L1 expression via IHC. First, there are multiple PD-L1 Fulvestrant (ICI 182,780) for IHC such as clones 28-8, 22C3, SP142, and SP263; of these, the consistency of three PD-L1 antibodies (all except for SP142) has been demonstrated for the assessment of tumor PD-L1 expression in several studies [[8], [9], [10]]. Second, the evaluation methods for PD-L1 expression involving thresholds and target cells differ depending on clinical trials [11,12]. Third, PD-L1 IHC does not satisfactorily identify responders and non-responders to PD-1/PD-L1 inhibitors [3,13]. Finally, one of the most critical issues is the heterogeneity of PD-L1 expression within and between tumors [[14], [15], [16], [17]]. To address these problems, alternative predictive factors of response to ICIs such as tumor mutation burden [18,19] and immune profiling in the tumor microenvironment [11,12] have been proposed. We previously reported the association of PD-L1 copy number alterations (CNAs) with PD-L1 protein expression levels and immune cell infiltration in NSCLC [20,21], and proposed that PD-L1 CNAs could potentially complement the predictive performance of PD-L1 expression [22]. Additionally, several reports have demonstrated the link between responses to ICIs and increases in PD-L1 gene copy number [[23], [24], [25], [26]]. Concordance of PD-L1 positivity between biopsy specimens and resected tumor specimens varied according to reports, primarily due to spatial heterogeneity as well as differences in biopsy methods [[14], [15], [16], [17],27]. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a relatively newly developed diagnostic modality that is becoming more relevant and essential in the clinical setting [28,29]. Previous limited studies have demonstrated the utility of the EBUS-TBNA procedure for the evaluation of PD-L1 protein expression [27,30]. However, it remains still elusive whether EBUS-TBNA is suitable for the evaluation of PD-L1 expression, particularly when heterogeneity is considered. Moreover, no data are currently available that demonstrate whether PD-L1 CNAs can be assessed using EBUS-TBNA-derived specimens and whether PD-L1 protein expression or copy number status is less spatially heterogeneous. Therefore, the first aim of this study was to evaluate the suitability of EBUS-TBNA-derived NSCLC biopsy specimens for the assessment of PD-L1 expression and gene copy number alterations, focusing on intertumoral heterogeneity using corresponding specimens obtained from other sites such as primary and metastasized tumors through different procedures such as surgery and transbronchial biopsy (TBB). The second aim was to compare the intratumoral heterogeneity of PD-L1 expression and CNAs. Our findings provide evidence that both PD-L1 protein expression and CNAs can be effectively assessed using EBUS-TBNA cores and that PD-L1 copy number status could represent a useful complementary biomarker of PD-L1 protein expression.
    Material and methods
    Results
    Discussion We here evaluated the concordance of PD-L1 protein expression and gene copy number between specimens obtained by EBUS-TBNA and other modalities including TBB, biopsy, and surgery. The applicability of EBUS-TBNA for the evaluation for PD-L1 protein expression in patients with NSCLC has been validated previously [27,30]. In addition, we found that PD-L1 copy number status is also evaluable in EBUS-TBNA-derived biopsy specimens using FISH. The concordance rates of PD-L1 expression and CNAs were comparable intertumorally. However, the concordance of PD-L1 expression decreased based on increasing cutoff values and intratumoral heterogeneity was more prominent in PD-L1 protein expression than in PD-L1 copy number status. These findings clearly indicated the limitation of the assessment of PD-L1 expression by IHC due to its heterogeneous nature.