title: Differentiation of CD8+ T cells from tumor-invaded and tumor-free lymph nodes of melanoma patients: role of common gamma-chain cytokines.
abstract: Differentiation of CD8(+) T cells at the tumor site toward effector and memory stages may represent a key step for the efficacy of antitumor response developing naturally or induced through immunotherapy. To address this issue, CD8(+) T lymphocytes from tumor-invaded (n = 142) and tumor-free (n = 42) lymph nodes removed from the same nodal basin of melanoma patients were analyzed for the expression of CCR7, CD45RA, perforin, and granzyme B. By hierarchical cluster analysis, CD8(+) T cells from all tumor-free lymph nodes and from 56% of the tumor-invaded lymph node samples fell in the same cluster, characterized mainly by CCR7(+) CD45RA(+/-) cytotoxic factor(-) cells. The remaining three clusters contained only samples from tumor-invaded lymph nodes and showed a progressive shift of the CD8(+) T cell population toward CCR7(-) CD45RA(-/+) perforin(+) granzyme B(+) differentiation stages. Distinct CD8(+) T cell maturation stages, as defined by CCR7 vs CD45RA and by functional assays, were identified even in melanoma- or viral Ag-specific T cells from invaded lymph nodes by HLA tetramer analysis. Culture for 7 days of CCR7(+) perforin(-) CD8(+) T cells from tumor-invaded lymph nodes with IL-2 or IL-15, but not IL-7, promoted, mainly in CCR7(+)CD45RA(-) cells, proliferation coupled to differentiation to the CCR7(-) perforin(+) stage and acquisition of melanoma Ag-specific effector functions. Taken together, these results indicate that CD8(+) T cells differentiated toward CCR7(-) cytotoxic factor(+) stages are present in tumor-invaded, but not in tumor-free, lymph nodes of a relevant fraction of melanoma patients and suggest that cytokines such as IL-2 and IL-15 may be exploited to promote Ag-independent maturation of anti-tumor CD8(+) T cells.
authors.affiliation: Human Tumor Immunobiology and Tumor Immunotherapy Units, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. andrea.anichini@istitutomori.mi.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Anichini
authors.forename: Alessia
authors.initials: A
authors.lastname: Scarito
authors.forename: Alessandra
authors.initials: A
authors.lastname: Molla
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.forename: Roberta
authors.initials: R
authors.lastname: Mortarini
mesh_terms: D000951:Antigens, Neoplasm; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000821:virology; D009363:Neoplasm Proteins / Q000276:immunology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D020395:Receptors, Interleukin-7 / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D000956:Antigens, Viral; C515370:CCR7 protein, human; D018984:Epitopes, T-Lymphocyte; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D007376:Interleukin-2; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D020395:Receptors, Interleukin-7