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• W2551752654 abstract "We read with interest the paper by Blaker et al (2016), which reported that several factors of the tumour microenvironment are associated with patient survival and time to transformation in follicular lymphoma (FL). In particular, the authors investigated the impact of PDCD1 (PD-1)-positive tumour infiltrating T-lymphocytes (TILs) and CD274 (PD-L1)-positive macrophages in a cohort of transformed FLs using a single antibody for CD274. However, the optimal method for immunohistochemical detection of CD274 either in macrophages or the lymphoma cells in routinely processed formalin-fixed, paraffin-embedded (FFPE) tissues remains a controversial issue in terms of the antibody and the platform used, the cutoffs that distinguish positive versus negative cases, as well as the method that best correlates with alterations of the CD274/PDCD1LG2 (PD-L2) gene locus (Georgiou et al, 2016) or transcriptional regulation of the gene (Ansell et al, 2015; Chen et al, 2016; Roemer et al, 2016). In addition, there is an urgent need for a consensus among pathologists, haematologists and oncologists regarding the CD274 status of patients recruited in clinical trials in the immunotherapy era (Sharma & Allison, 2015). We examined the expression levels of CD274 in a series of FFPE diagnostic samples from 31 patients with diffuse large B-cell lymphoma (DLBCL), including 20 de novo and 11 transformed (from FL) tumours diagnosed and treated at Karolinska University Hospital (Stockholm, Sweden). DLBCLs were diagnosed according to the World Health Organization 2008 classification and classified as germinal centre (GC) or non-GC type according to the Hans algorithm (Hans et al, 2004). All DLBCL patients were uniformly treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with median follow-up 105 months. A tissue microarray (TMA) was constructed using duplicate tumour cores from each DLBCL, 2 follicular lymphomas (FL) and 2 reactive lymph nodes. Use of the patient samples was previously approved by the Karolinska Institutet's Ethical Committee. Two antibodies, Ventana SP142 (US Food and Drug Administration-approved assay; Roche, Tucson, AZ, USA) and E1L3N (Cell Signaling, Beverly, MA, USA), recently utilized in other DLBCL series (Georgiou et al, 2016; Menter et al, 2016), were used. The percentage of CD274+ lymphoma cells was calculated by counting at least 1000 tumour cells in each case with no cutoff for positivity used. Based on the distribution of data (histogram), four groups were clearly defined for CD274 in tumour cells: negative (no CD274+ cells), low expression (<5% positive), moderate expression (5–30% positive) and high expression (>30% positive). Only membrane staining was considered positive. In reactive lymph nodes, CD274 was expressed by histiocytes mostly in the follicles. PDCD1 protein was expressed by T-cells in reactive follicles and interfollicular zones. The two different CD274 antibodies showed different results in tumour cells: using SP142 or E1L3N, one case (1/31, 3·2%) was strongly and homogenously positive for CD274 (100% of tumour cells) (Fig 1). This strong expression correlated with CD274 gene amplification as demonstrated by fluorescence in situ hybridization (FISH) using a probe specific for the CD274/PDCD1LG2 gene locus (Zytovision, Bremerhaven, Germany) previously validated in our research laboratory (Fig S1). Of note, the described case was classified as CD30+ DLBCL, not otherwise specified, anaplastic variant, with non-GC phenotype, associated with 100% cell proliferation (Ki67) and two “hot spot” TP53 mutations in exon 7. Moreover, targeted next generation sequencing performed on this case showed no mutations of other genes including MYD88, KRAS, PIK3CA, BRAF, AKT1, PTEN, NOTCH1, or FBXW7 (not shown). The comparison between the two antibodies is shown in Table S1: Low CD274 expression was found in 2/31 (6·5%) and 14/31 (45·2%) cases with SP142 and E1L3N, respectively. Moderate CD274 expression was observed in none (0%) and 3/31 (9·7%) cases assessed with SP142 and E1L3N, respectively. Therefore, the two antibodies differ significantly in sensitivity, as E1L3N detected many more positive cases with low and moderate CD274 expression in tumour cells. On the other hand, SP142 demonstrated stronger and more specific CD274 expression in histiocytes as compared to E1L3N. Knowledge of the differences in sensitivity of CD274 detection methods is important for the design and optimal selection of patients for immunotherapy clinical trials, (Sharma & Allison, 2015) but also important for predictive and prognostic studies in DLBCL.(Dong et al, 2016) Also, we found that CD274 expression was more often associated with de novo DLBCL as compared to transformed DLBCL (15/20 or 75% versus 3/11 or 27·3%, P = 0·02, Fisher's exact test) and showed a statistical tendency towards higher frequency in patients with non-GC versus GG phenotype of DLBCLs (P = 0·052, Chi-Square test). CD274 expression by the tumour cells correlated with tumour proliferation assessed by Ki67 (MIB-1) (P = 0·016, Mann Whitney U test, Fig 2). Notably, decreased numbers of PDCD1 positive TILs were also associated with high tumour cell proliferation (P = 0·015, Mann Whitney U test, Fig 2). Interestingly, the numbers of PDCD1 positive TILs were statistically associated with CD274 expression in histiocytes (P = 0·018, Chi-Square test) but not with CD274 levels in tumour cells, suggesting possible interactions between tumour microenvironment cells.(Sharma & Allison, 2015) Furthermore, increased numbers of CD274 positive histiocytes correlated with superior overall survival (P = 0·049 by Kaplan-Mayer method and Log rank test, Fig 2) despite the small number of patients in this cohort. Blaker et al (2016) reported that high numbers of intrafollicular CD68+ and CD274+ histiocytes correlated with shorter time to transformation of FL but not with survival of the patients. In summary, although in general agreement with previous reports (Kiyasu et al, 2015; Blaker et al, 2016; Georgiou et al, 2016; Menter et al, 2016), our data expand substantially on those studies. We show for the first time that, in DLBCL, the SP142 antibody correlates in an absolute manner with CD274/PDCD1LG2 gene amplification status assessed by FISH, but generally fails to detect low/moderate levels of the protein. CD274 expression assessed by two different antibodies may be better associated with tumour biology (i.e. proliferation) and selection of patients for investigational immunotherapy. Additionally, assessment of CD274 positive histiocytes and PDCD1 positive TILs may be of prognostic significance and should be further investigated in large cohorts of patients with de novo or transformed DLBCL. The authors are grateful to Mrs. Ann Kaufeldt and Ann Onlson for providing excellent technical assistance for immunohistochemistry and FISH analysis, respectively. A. Kwiecinska performed research, analysed data and contributed to the writing of the paper; N. Tsesmetzis, M. Ghaderi and Lorand Kis performed research. Leonie Saft contributed clinical samples and also contributed to the writing of the paper. G. Z. Rassidakis conceived the hypothesis, designed research, analysed data and contributed to the writing of the paper. Fig S1. The immunohistochemical methods (IHC) and fluorescence in situ hybridization analysis (FISH) were validated in our research and diagnostic laboratories using a Hodgkin lymphoma cell line (HDML2) and tissue specimens from patients with classical Hodgkin lymphoma. Table SI. Comparison of two different PD-L1 antibodies for various PD-L1 expression levels in DLBCL. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2551752654 date "2016-11-23" @default.
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• W2551752654 title "CD274 (PD-L1)/PDCD1 (PD-1) expression in de novo and transformed diffuse large B-cell lymphoma" @default.
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