title: Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature.
abstract: The presence of tumor-infiltrating immune cells is associated with longer survival and a better response to immunotherapy in early-stage melanoma, but a comprehensive study of the in situ immune microenvironment in stage IV melanoma has not been performed. We investigated the combined influence of a series of immune factors on survival and response to adoptive cell transfer (ACT) in stage IV melanoma patients. Metastases of 73 stage IV melanoma patients, 17 of which were treated with ACT, were studied with respect to the number and functional phenotype of lymphocytes and myeloid cells as well as for expression of galectins-1, -3, and -9. Single factors associated with better survival were identified using Kaplan-Meier curves and multivariate Cox regression analyses, and those factors were used for interaction analyses. The results were validated using The Cancer Genome Atlas database. We identified four parameters that were associated with a better survival: CD8+T cells, galectin-9+dendritic cells (DC)/DC-like macrophages, a high M1/M2 macrophage ratio, and the expression of galectin-3 by tumor cells. The presence of at least three of these parameters formed an independent positive prognostic factor for long-term survival. Patients displaying this four-parameter signature were found exclusively among patients responding to ACT and were the ones with sustained clinical benefit. Cancer Immunol Res; 5(2); 170-9. ©2017 AACR.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Melief
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Valeria V
authors.initials: VV
authors.lastname: Visconti
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marten
authors.initials: M
authors.lastname: Visser
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Merel
authors.initials: M
authors.lastname: van Diepen
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Ellen H W
authors.initials: EH
authors.lastname: Kapiteijn
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Joost H
authors.initials: JH
authors.lastname: van den Berg
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Bioinformatics Center of Expertise, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Oosting
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands. e.verdegaal@lumc.nl.
authors.forename: Els M E
authors.initials: EM
authors.lastname: Verdegaal
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers; D005260:Female; D037161:Galectins / Q000378:metabolism; D006801:Humans; D007109:Immunity; D016219:Immunotherapy, Adoptive; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D037161:Galectins