title: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Xinqi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Anita
authors.initials: A
authors.lastname: Giobbie-Hurder
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Courtney
authors.initials: C
authors.lastname: Connelly
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.|Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Connolly
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manos
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Donald
authors.initials: D
authors.lastname: Lawrence
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: McDermott
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Mariano
authors.initials: M
authors.lastname: Severgnini
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Evisa
authors.initials: E
authors.lastname: Gjini
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ana
authors.initials: A
authors.lastname: Lako
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Mikel
authors.initials: M
authors.lastname: Lipschitz
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Pak
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sara
authors.initials: S
authors.lastname: Abdelrahman
authors.affiliation: Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. stephen_hodi@dfci.harvard.edu.|Center for Immuno-oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.|Melanoma Disease Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
mesh_terms: D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D016019:Survival Analysis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D042702:Angiopoietin-2; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D061026:Programmed Cell Death 1 Receptor; D042461:Vascular Endothelial Growth Factor A