Importance Four assays have been registered with the FDA to detect PD-L1 to enrich for patient response to anti-PD-1/PD-L1 therapies. The tests use four separate PD-L1 antibodies on two separate staining platforms and have their own scoring systems which raises questions about their similarity and potential cross-utilization. Objective We compared the performance of four PD-L1 platforms, including two FDA-cleared assays and two laboratory developed tests (LDTs). Design Four serial histology sections from 90 archival NSCLCs were distributed to three sites that performed the following IHCs: 1) 28-8 antibody on Dako Link 48; 2) 22c3 antibody on Dako Link 48; 3) SP142 antibody on Ventana Benchmark; and 4) E1L3N antibody on Leica Bond. Slides were scanned and scored by thirteen pathologists by estimating the percentage of malignant and immune cells expressing PD-L1. Intraclass correlation coefficients (ICC) and paired and mixed effects statistical analyses were performed to compare antibodies and pathologists scoring of tumor and immune cells. Results The SP142 Ventana assay was an outlier with a significantly lower mean score of PD-L1 expression in both tumor and immune cells. Pairwise comparisons showed the 28-8 and E1L3N were not significantly different, but that 22c3 showed a slight but statistically significant reduction in tumor cell labeling. Evaluation of ICC between antibodies to quantify inter-assay variability using the average of thirteen pathologists scores for tumor shows very high concordance between antibodies for tumor cell scoring (0.813) and lower levels of concordance for immune cell scoring (0.277). When examining inter-pathologists variability for any single antibody, the concordance between pathologists’ reads for tumor ranged from ICC of 0.83 to 0.88 for each antibody while the ICC from immune cells for each antibody ranged from 0.17 to 0.23. Conclusions The assay using the SP142 antibody is a clear outlier detecting significantly less tumor cell and immune cell PD-L1 expression. Antibody 22c3 shows slight yet statistically significantly lower staining than either 28-8 or E1L3N, but this significance is only detected when using the average of thirteen pathologist scores. Pathologists show excellent concordance when scoring tumor cells stained with any antibody, but poor concordance for scoring immune cell staining.
Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.
Introduction Therapeutic antibodies to immune checkpoints show promising results. Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD-L1 receptor (programmed death 1). We investigated PD-L1 protein expression and messenger RNA (mRNA) levels in SCLC. Methods PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28-8 PD-L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor-infiltrating immune cells (TIICs) obtained from a limited-disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive-disease SCLC was assessed for PD-L1 protein expression in tumor cells with Dako 28-8 antibody only. Results The overall prevalence of PD-L1 protein expression in tumor cells was 16.5%. In the limited-disease cohort, the prevalences of PD-L1 protein expression in tumor cells with SP142 and Dako 28-8 were 14.7% and 19.4% (tumor proportion score cutoff ≥1%) and PD-L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD-L1 protein/mRNA expression was associated with the presence of more TIICs (p < 0.05). The extensive-disease cohort demonstrated a 14.9% positivity of PD-L1 protein expression in tumor cells with Dako 28-8 antibody. Conclusions A subset of SCLCs is characterized by positive PD-L1 and/or mRNA expression in tumor cells. Higher PD-L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD-L1 in SCLC is lower than that published for NSCLC. The predictive role of PD-L1 expression in SCLC treatment remains to be established.
Oncolytic viruses designed to attack malignant cells can in addition infect and destroy tumor vascular endothelial cells. We show here that this expanded tropism of oncolytic vaccinia virus to the endothelial compartment is a consequence of VEGF-mediated suppression of the intrinsic antiviral response. VEGF/VEGFR2 signaling through Erk1/2 and Stat3 leads to upregulation, nuclear localization, and activation of the transcription repressor PRD1-BF1/Blimp1. PRD1-BF1 does not contribute to the mitogenic effects of VEGF, but directly represses genes involved in type I interferon (IFN)-mediated antiviral signaling. In vivo suppression of VEGF signaling diminishes PRD1-BF1/Blimp1 expression in tumor vasculature and inhibits intravenously administered oncolytic vaccinia delivery to and consequent spread within the tumor.
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