Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE198269 | GEO | 2022/03/14
REPOSITORIES: GEO
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Project description:<p>Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.</p>
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Project description:Programmed death-ligand 1 (PD-L1) expression has been associated with response to PD-1/PD-L1 inhibition, but responses are also seen in patients with PD-L1 negative tumors when assessed immunohistochemically (IHC) with various antibodies. To help elucidate these findings, we performed a positron emission tomography (PET) imaging study in human with the anti-PD-L1 antibody atezolizumab labeled with Zirconium-89 (89Zr) prior to treatment with atezolizumab to assess normal tissue distribution and evaluate tumor tracer uptake. Additionally, to help explain why some patients respond to checkpoint inhibitors despite low or absent PD-L1 expression, we compared PD-L1 expression and immune phenotypes based on both CD8 IHC and RNA sequencing of post-tracer biopsies to tumor tracer uptake (SUVmax).
2018-06-12 | GSE115594 | GEO
Project description:An unmet need in cancer treatment is identification of biomarkers of response to PD-1 or PD-L1 immune checkpoint inhibitors that predict therapeutic outcomes in patients with non–small-cell lung carcinoma (NSCLC) and urothelial cancer (UC). Expression of PD-L1 measured by immunohistochemistry has limited capacity for predicting outcomes of immune checkpoint therapy because expression of this biomarker does not correlate highly with treatment response. In addition, PD-L1 as measured on tumor cells, which has been approved by the FDA for both companion and complementary diagnostic utility, does not necessarily reflect anti-tumor activity of tumor-infiltrating lymphocytes. Results presented in this report demonstrate that gene expression levels of four interferon gamma (IFNγ)-inducible mRNAs correlate with improved clinical outcomes in patients with NSCLC or UC treated with the PD-L1 inhibitor durvalumab. This IFNγ gene signature may augment the predictive value of PD-L1 and other biomarkers in identifying cancer patients most likely to respond to therapy with durvalumab or other immune checkpoint inhibitors.
2018-02-14 | GSE110390 | GEO
Project description:Thirty-eight tumors from 17 patients treated with BRAF inhibitor (n=12) or combination BRAF/MEK inhibitors (n=5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pre-treatment (PRE, n=17), early during treatment (EDT, n=8) and progression (PROG, n=13) biopsies. HLA-A/HLA-DPB1 expression was assessed by immunohistochemistry (IHC). Gene set enrichment analysis (GSEA) of PRE, EDT and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-ß-catenin activity were negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition.
2017-07-01 | GSE99898 | GEO
Project description:New therapeutics targeting immune checkpoint proteins have significantly advanced treatment of non-small cell lung cancer (NSCLC), but protein level quantitation of drug targets presents a critical problem. We used multiplexed, targeted mass spectrometry (MS) to quantify the immunotherapy target proteins PD-1, PD-L1, PD-L2, IDO1, LAG3, TIM-3, VISTA, GITR, and CD40 in formalin-fixed, paraffin-embedded (FFPE) NSCLC specimens. Immunohistochemistry (IHC) and MS measurements for PD-L1 were weakly correlated, but IHC did not distinguish protein abundance differences detected by MS. PD-L2 abundance exceeded PD-L1 in over half the specimens and the drug target proteins all displayed different abundance patterns. mRNA correlated with protein abundance only for PD-1, PD-L1, and IDO1 and tumor mutation burden did not predict abundance of any protein targets. Global proteome analyses identified distinct proteotypes associated with high PD-L1-expressing and high IDO1-expressing NSCLC. MS quantification of multiple drug targets and tissue proteotypes can improve clinical evaluation of immunotherapies for NSCLC.
2020-06-22 | PXD019061 | panorama
Project description:Background: Immune checkpoint blockade improves survival in a subset of patients with non-small cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. Methods: We performed comprehensive flow-cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC). Results: Cytometric profiling identified an immunologically “hot” cluster with abundant CD8+ T cells expressing high levels of the PD-1 and TIM-3, and an immunologically “cold” cluster with lower relative abundance of CD8+ T cells and expression of inhibitory markers. The “hot” cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function, and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the “hot” cluster. Additionally, ~20% of cases had high B cell infiltrates with a subset producing IL-10. Conclusions: Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer. Background: Immune checkpoint blockade improves survival in a subset of patients with non-small cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. Methods: We performed comprehensive flow-cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC). Results: Cytometric profiling identified an immunologically “hot” cluster with abundant CD8+ T cells expressing high levels of the PD-1 and TIM-3, and an immunologically “cold” cluster with lower relative abundance of CD8+ T cells and expression of inhibitory markers. The “hot” cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function, and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the “hot” cluster. Additionally, ~20% of cases had high B cell infiltrates with a subset producing IL-10. Conclusions: Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer.
2016-10-11 | GSE84789 | GEO
Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.
2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress
Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.
2022-03-31 | MSV000089180 | MassIVE
Project description:Background: Immune checkpoint blockade improves survival in a subset of patients with non-small cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. Methods: We performed comprehensive flow-cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC). Results: Cytometric profiling identified an immunologically “hot” cluster with abundant CD8+ T cells expressing high levels of the PD-1 and TIM-3, and an immunologically “cold” cluster with lower relative abundance of CD8+ T cells and expression of inhibitory markers. The “hot” cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function, and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the “hot” cluster. Additionally, ~20% of cases had high B cell infiltrates with a subset producing IL-10. Conclusions: Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer. Background: Immune checkpoint blockade improves survival in a subset of patients with non-small cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. Methods: We performed comprehensive flow-cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC). Results: Cytometric profiling identified an immunologically “hot” cluster with abundant CD8+ T cells expressing high levels of the PD-1 and TIM-3, and an immunologically “cold” cluster with lower relative abundance of CD8+ T cells and expression of inhibitory markers. The “hot” cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function, and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the “hot” cluster. Additionally, ~20% of cases had high B cell infiltrates with a subset producing IL-10. Conclusions: Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer. 29 NSCLC cases analyzed wth Nanostring human PanCancer immune module
2016-10-11 | GSE84797 | GEO
Project description:Background: Recent data demonstrated efficacy of immune checkpoint inhibitors in advanced OCCC, but little is known about the immune microenvironment of these tumours and its impact on outcomes. We studied the expression of a panel of immune response genes in OCCC to identify the presence and prognostic relevance of irGES in these tumours. Methods: Immune response gene profiling was performed on 96 FFPE OCCC tumour samples with matched clinical outcomes, collected from the National University Hospital, Singapore between 2003 – 2016, using the nanoString nCounter PanCancer Immune Profiling Panel. Unsupervised hierarchical clustering analysis was performed to stratify OCCCs to derive the irGES profiles. Upregulation of specific genes of interest at the protein level and the status of mismatch repair (MMR) and ARID1A were validated using immunohistochemistry (IHC). Results: Total of 74/84 samples were successfully profiled. Median age at diagnosis was 53 yrs. 41 (55.4%) were stage 1, 7 (9.5%) stage 2, 24 (32.4%) Stage3, 2 (2.7%) stage 4. 64/74 (86.5%) of patients received adjuvant chemotherapy post debulking surgery with 38% recurrence rate (median PFS 27 months). Median follow up was 36 months. Based on irGES, 4 distinct molecular subgroups of OCCCs were identified. G1 was hallmarked by NK cell markers and PD-1 expression (PD-1 high), G2 by increased CTLA-4 expression, G3 by upregulation of genes associated with immunogenicity and antigen presentation, and G4 by increased levels of pro - angiogenic genes. The PD-1 high group was observed to have significantly poorer PFS (median PFS 20 months vs 68 months, p= 0.011) and a trend towards poorer OS when compared with G2/3/4 (median OS 38.8 months vs undefined, p = 0.0501). The pro - angiogenic (G4) carried the best prognosis (median PFS 108 months vs 26 months, p= 0.0515; median OS undefined, p= 0.0726). This difference in OS and PFS was consistently observed between stage 1 and non-stage 1 pts (hazard ratio 5.856 and 5.659, p < 0.0001, respectively). Significant correlation was observed between gene and protein expression of tumour PD-1, tumour and stromal PD-L1, and tumour IL-6 using IHC (p < 0.0001 for all comparisons). 6 (8.1%) pts were MMR deficient and there was no significant association between ARID1A and MMR expression across each irGES groups. Conclusion: OCCCs are heterogeneous and can be classified into 4 molecular subgroups based on their irGES profiles representing distinct clinicopathological characteristics and prognostic outcomes. If validated in larger datasets, these signatures may serve to guide clinical trial design and personalized treatment for OCCC pts.
2021-08-27 | GSE128990 | GEO