title: Recurrence of melanoma following T cell treatment: continued antigen expression in a tumor that evades T cell recruitment.
abstract: Clinical therapy with T cells shows promise for cancer patients, but is currently challenged by incomplete responses and tumor relapse. The exact mechanisms that contribute to tumor relapse remain largely unclear. Here, we treated mouse melanomas with T cell receptor-engineered T cells directed against a human peptide-major histocompatibility complex antigen in immune-competent mice. T cells resulted in significant tumor regression, which was followed by relapse in about 80-90% of mice. Molecular analysis revealed that relapsed tumors harbored nonmutated antigen genes, not silenced by promoter methylation, and functionally expressed surface antigen at levels equal to nontreated tumors. Relapsed tumors resisted a second in vivo T cell treatment, but regained sensitivity to T cell treatment upon retransplantation in mice. Notably, relapsed tumors demonstrated decreased levels of CD8 T cells and monocytes, which were substantiated by downregulated expression of chemoattractants and adhesion molecules. These observations were confirmed when using T cells specific for a less immunogenic, endogenous mouse melanoma antigen. We conclude that tumors, when exposed to T cell treatment, can relapse without loss of antigen and develop a milieu that evades recruitment of effector CD8 T cells. Our findings support the concept to target the tumor milieu to aid T cell therapy in limiting tumor relapse.
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Trudy
authors.initials: T
authors.lastname: Straetemans
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Berrevoets
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Coccoris
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Elike
authors.initials: E
authors.lastname: Treffers-Westerlaken
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wijers
authors.affiliation: Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.affiliation: Institute de Génétique Moléculaire de Montpellier, Université Montpellier, Montpellier, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Dardalhon
authors.affiliation: Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.affiliation: Institute de Génétique Moléculaire de Montpellier, Université Montpellier, Montpellier, France.
authors.forename: Naomi
authors.initials: N
authors.lastname: Taylor
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D019175:DNA Methylation; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte; D015870:Gene Expression; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008546:Melanoma, Experimental; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell