title: Immune-escape markers in relation to clinical outcome of advanced melanoma patients following immunotherapy.
abstract: In this study, we investigated a large series of immune (escape) markers, relevant to T-cell function, as potential biomarkers for clinical outcome following immunotherapy. We retrospectively studied the expression of immune (escape) markers in metastatic melanoma tissues of 27 patients before autologous tumor cell vaccination, and 16 patients who were intended to treat but were not vaccinated because of rapid disease progression. Immunohistochemical data of infiltrating (suppressive) cells, such as T cells, regulatory T cells, myeloid-derived suppressor cells, and mast cells, or the expression of T-cell inhibitory factors (PD-1/PD-L1, IDO, and galectins), cytotoxic molecules (granzyme-B), melanocyte differentiation antigens, HLA class-I and tolerogenic cytokines [interleukin (IL)-1, IL-6, IL-10, TNF-α, and TGF-β] were correlated statistically to clinical outcome and overall survival (OS). Significantly more tumor-infiltrating CD4(+) and CD8(+) T cells (both P < 0.05) were found in nonprogressors to vaccination (n = 9; median OS, 56 months), compared with progressors (n = 18; median OS, 9.5 months). Moreover, granzyme-B expression was elevated in the tumors of nonprogressors, suggesting activated cytotoxic T cells or natural killer cells. T-cell infiltration and granzyme-B expression significantly correlated with overall OS. T-cell inhibitory factors and suppressive cells did not correlate with OS, suggesting minor influence of these immune-escape markers on clinical outcome. The data of progressors were comparable with those from patients with rapid progression (not vaccinated; n = 16; median OS, 3 months). Our study shows that high numbers of intratumoral activated CD4(+) or CD8(+) T cells, before autologous tumor cell vaccination, are associated with favorable clinical outcome. Analyses of these markers in the patients' tumor tissues before immunotherapy may therefore be a valuable tool to select patients for whom the treatment may result in potential clinical benefit.
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands e.p.tjin@amc.uva.nl.
authors.forename: Esther P M
authors.initials: EP
authors.lastname: Tjin
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Krebbers
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Meijlink
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Willeke
authors.initials: W
authors.lastname: van de Kasteele
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Efraim H
authors.initials: EH
authors.lastname: Rosenberg
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Joyce
authors.initials: J
authors.lastname: Sanders
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Petra M
authors.initials: PM
authors.lastname: Nederlof
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Bart A
authors.initials: BA
authors.lastname: van de Wiel
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the NetherlandsAuthors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Florry A
authors.initials: FA
authors.lastname: Vyth-Dreese
authors.affiliation: Authors' Affiliations: Department of Dermatology, Academic Medical Center, University of Amsterdam; Department of Pathology; Molecular Diagnostic Laboratory; Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Clinical Oncology, Leiden University Medical Center, Leiden University; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Rosalie M
authors.initials: RM
authors.lastname: Luiten
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D019496:Cancer Vaccines / Q000627:therapeutic use; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; D008565:Membrane Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human