Dataset Information

Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.

ABSTRACT: Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody bevacizumab. We investigated the predictive and prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with reduced overall survival in CTLA-4 and PD-1 blockade-treated patients. These treatments also increased serum ANGPT2 in many patients early after treatment initiation, whereas ipilimumab plus bevacizumab treatment decreased serum concentrations. ANGPT2 increases were associated with reduced response and/or overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab decreased, tumor vascular ANGPT2 expression in a subset of patients, which was associated with increased and decreased tumor infiltration by CD68+ and CD163+ macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting and functional antibody responses to ANGPT2 in a subset of patients receiving clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a predictive and prognostic biomarker for immune checkpoint therapy and may contribute to treatment resistance via increasing proangiogenic and immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2 provides a rational combinatorial approach to improve the efficacy of immune therapy. Cancer Immunol Res; 5(1); 17-28. ©2016 AACR.

SUBMITTER: Wu X

PROVIDER: S-EPMC5215959 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.

Wu Xinqi X Giobbie-Hurder Anita A Liao Xiaoyun X Connelly Courtney C Connolly Erin M EM Li Jingjing J Manos Michael P MP Lawrence Donald D McDermott David D Severgnini Mariano M Zhou Jun J Gjini Evisa E Lako Ana A Lipschitz Mikel M Pak Christine J CJ Abdelrahman Sara S Rodig Scott S Hodi F Stephen FS

Cancer immunology research 20161221 1

Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody ...[more]

PMID: 28003187

Similar Datasets

Project description:BackgroundImmune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy.MethodsWe tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data.ResultsWe collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets.ConclusionsOur findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.

Project description:An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing (WXS) or using commercially available sequencing panels.WXS and RNA-seq data of 33 solid cancer types from TCGA were analyzed to determine whether a robust immune checkpoint activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker for response to immune checkpoint blockade therapy.We find that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in 8 of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, ER+HER2- breast cancer, and bladder-urothelial cancer. Tumors with mutational burden higher than the threshold (iCAM+) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma and colon cancer, patients with iCAM+ tumors had significantly better response to immune checkpoint therapy compared to those with iCAM- tumors. ROC analysis using TCGA predictions as gold standard showed that iCAM+ tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne or StrandAdvantage. Using the FoundationOne derived threshold, analysis of 113 melanoma tumors, showed that iCAM+ patients have significantly better response to immune checkpoint therapy. iCAM+ and iCAM- tumors have distinct mutation patterns and different immune microenvironments.In 8 solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.

Dataset Information

Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.

Publications

Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets