title: Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells.
abstract: The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor-host interactions, we evaluated three syngeneic murine tumor models, the BRAFV600E-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAFV600Emutation and PTEN loss (BRAFV600E/PTEN-/-). Anti-PD-1 or anti-PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1, but not YUMM1.1. PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation. Whereas mutational load was high in MC38, it was lower in both YUMM models. In YUMM2.1, the antitumor activity of PD-1 blockade had a critical requirement for both CD4 and CD8 T cells, as well as CD28 and CD80/86 costimulation, with an increase in CD11c+CD11b+MHC-IIhighdendritic cells and tumor-associated macrophages in the tumors after PD-1 blockade. Compared with YUMM1.1, YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis, with an increase in expression of chemokine-trafficking genes that are related to immune cell recruitment and T-cell priming. In conclusion, response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages. Cancer Immunol Res; 4(10); 845-57. ©2016 AACR.
authors: Division of Hematology/Oncology, Department of Medicine, University of California (UCLA), Los Angeles, California.
authors: Blanca
authors: B
authors: Homet Moreno
authors: Division of Hematology/Oncology, Department of Medicine, University of California (UCLA), Los Angeles, California. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California.
authors: Jesse M
authors: JM
authors: Zaretsky
authors: Division of Hematology/Oncology, Department of Medicine, University of California (UCLA), Los Angeles, California.
authors: Angel
authors: A
authors: Garcia-Diaz
authors: Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California.
authors: Jennifer
authors: J
authors: Tsoi
authors: Division of Hematology/Oncology, Department of Medicine, University of California (UCLA), Los Angeles, California.
authors: Giulia
authors: G
authors: Parisi
authors: Division of Hematology/Oncology, Department of Medicine, University of California (UCLA), Los Angeles, California.
authors: Lidia
authors: L
authors: Robert
authors: Departments of Immunobiology, Dermatology, and Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors: Katrina
authors: K
authors: Meeth
authors: Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors: Abibatou
authors: A
authors: Ndoye
authors: Departments of Immunobiology, Dermatology, and Pathology, Yale University School of Medicine, New Haven, Connecticut. Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors: Marcus
authors: M
authors: Bosenberg
authors: Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.
authors: Ashani T
authors: AT
authors: Weeraratna
authors: Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center (JCCC) at UCLA, Los Angeles, California.
authors: Thomas G
authors: TG
authors: Graeber
authors: Jonsson Comprehensive Cancer Center (JCCC) at UCLA, Los Angeles, California. Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, California.
authors: Begoña
authors: B
authors: Comin-Anduix
authors: Division of Hematology/Oncology, Department of Medicine, University of California (UCLA), Los Angeles, California. Jonsson Comprehensive Cancer Center (JCCC) at UCLA, Los Angeles, California. aribas@mednet.ucla.edu shu-lieskovan@mednet.ucla.edu.
authors: Siwen
authors: S
authors: Hu-Lieskovan
authors: Division of Hematology/Oncology, Department of Medicine, University of California (UCLA), Los Angeles, California. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center (JCCC) at UCLA, Los Angeles, California. Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, California. aribas@mednet.ucla.edu shu-lieskovan@mednet.ucla.edu.
authors: Antoni
authors: A
authors: Ribas
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL; D009154:Mutation; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C000594389:atezolizumab; D007371:Interferon-gamma; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf