title: The therapeutic T-cell response induced by tumor delivery of TNF and melphalan is dependent on early triggering of natural killer and dendritic cells.
abstract: The fusion protein L19mTNF (mouse TNF and human antibody fragment L19 directed to fibronectin extra domain B) selectively targets the tumor vasculature, and in combination with melphalan induces a long-lasting T-cell therapeutic response and immune memory in murine models. Increasing evidence suggests that natural killer (NK) cells act to promote effective T-cell-based antitumor responses. We have analyzed the role of NK cells and dendritic cells (DCs) on two different murine tumor models: WEHI-164 fibrosarcoma and C51 colon carcinoma, in which the combined treatment induces high and low rejection rates, respectively. In vivo NK-cell depletion strongly reduced the rejection of WEHI-164 fibrosarcoma and correlated with a decrease in mature DCs, CD4+, and CD8+T cells in the tumor-draining LNs and mature DCs and CD4+T cells in the tumor 40 h after initiation of the therapy. NK-cell depletion also resulted in the impairment of the stimulatory capability of DCs derived from tumor-draining LNs of WEHI-164-treated mice. Moreover, a significant reduction of M2-type infiltrating macrophages was detected in both tumors undergoing therapy. These results suggest that the efficacy of L19mTNF/melphalan therapy is strongly related to the early activation of NK cells and DCs, which are necessary for an effective T-cell response.
authors.affiliation: Cell Biology Unit, Department of Integrated Oncological Therapies, IRCSS AOU San Martino Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Balza
authors.affiliation: Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.|Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zanellato
authors.affiliation: Molecular Oncology and Angiogenesis Unit, IRCCS AOU San Martino IST, Genoa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.affiliation: Molecular Pathology Unit, IRCCS AOU San Martino IST, Genoa, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Reverberi
authors.affiliation: Cell Biology Unit, Department of Integrated Oncological Therapies, IRCSS AOU San Martino Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
authors.affiliation: Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Mortara
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005354:Fibrosarcoma / Q000188:drug therapy*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008558:Melphalan / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; C558733:L19mTNFalpha protein; D011993:Recombinant Fusion Proteins; D008558:Melphalan
keywords: Antitumor therapy; Dendritic cell; L19; Melphalan; Natural killer cell; TNF