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: Enrica Balza, Silvia Zanellato, Alessandro Poggi, Daniele Reverberi, Anna Rubartelli, Lorenzo Mortara
• Journal: European journal of immunology (Eur J Immunol) Vol. 47 Issue 4 Pg. 743-753 (04 2017) ISSN: 1521-4141 [Electronic] Germany
• PMID: 28198545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents, Alkylating
• L19mTNFalpha protein
• Recombinant Fusion Proteins
• Melphalan

Topics

• Animals
• Antineoplastic Agents, Alkylating (therapeutic use)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• Cell Differentiation
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy)
• Dendritic Cells (drug effects, immunology)
• Disease Models, Animal
• Drug Therapy, Combination
• Fibrosarcoma (drug therapy)
• Humans
• Killer Cells, Natural (drug effects, immunology)
• Lymphocyte Activation
• Lymphocyte Depletion
• Melphalan (therapeutic use)
• Mice
• Mice, Inbred BALB C
• Recombinant Fusion Proteins (therapeutic use)
• T-Lymphocytes, Cytotoxic (drug effects, immunology)
• Tumor Burden (drug effects)