title: Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases.
abstract: Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases.
  
  
  
  Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression.
  
  
  
  Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures.
  
  
  
  The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases.
authors: Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Ileana S
authors: IS
authors: Mauldin
authors: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors: Nolan A
authors: NA
authors: Wages
authors: Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Anne M
authors: AM
authors: Stowman
authors: Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors: Ena
authors: E
authors: Wang
authors: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors: Mark E
authors: ME
authors: Smolkin
authors: Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Walter C
authors: WC
authors: Olson
authors: Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Donna H
authors: DH
authors: Deacon
authors: Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Kelly T
authors: KT
authors: Smith
authors: Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Nadedja V
authors: NV
authors: Galeassi
authors: Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Kimberly A
authors: KA
authors: Chianese-Bullock
authors: Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
authors: Lynn T
authors: LT
authors: Dengel
authors: Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors: Francesco M
authors: FM
authors: Marincola
authors: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
authors: Gina R
authors: GR
authors: Petroni
authors: Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors: David W
authors: DW
authors: Mullins
authors: Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA. cls8h@virginia.edu.
authors: Craig L
authors: 0000-0002-6664-4373
authors: CL
authors: Slingluff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002465:Cell Movement; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000378:metabolism*; D054371:Chemokine CXCL11 / Q000378:metabolism*; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009367:Neoplasm Staging; D010446:Peptide Fragments / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; C483024:CCL5 protein, human; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; D019496:Cancer Vaccines; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D007155:Immunologic Factors; D010446:Peptide Fragments; D022223:Vaccines, Subunit; D007371:Interferon-gamma
keywords: Human; Immunotherapy; Interferon-gamma; Melanoma; T lymphocytes; Tumor vaccines