The therapeutic T-cell response induced by tumor delivery of TNF and melphalan is dependent on early triggering of natural killer and dendritic cells
| Autor: | Anna Rubartelli, Lorenzo Mortara, Silvia Zanellato, Daniele Reverberi, Alessandro Poggi, Enrica Balza |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Melphalan CD4-Positive T-Lymphocytes Fibrosarcoma Recombinant Fusion Proteins Immunology Natural killer cell TNF Antitumor therapy Dendritic cell L19 Lymphocyte Activation Lymphocyte Depletion 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor medicine Immunology and Allergy Animals Humans Antineoplastic Agents Alkylating Mice Inbred BALB C Lymphokine-activated killer cell biology Cell Differentiation Dendritic Cells medicine.disease Tumor Burden Killer Cells Natural Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research biology.protein Tumor necrosis factor alpha Drug Therapy Combination Antibody Colorectal Neoplasms CD8 medicine.drug T-Lymphocytes Cytotoxic |
| Zdroj: | European journal of immunology. 47(4) |
| ISSN: | 1521-4141 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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