PURPOSE: A systemic administration of L19mTNFa selectively targets the tumor vasculature, and in combination with melphalan is able to induce a long-lasting therapeutic response and immune T cell memory in two tumor mice models: WEHI-164 fibrosarcoma, that respond well to the therapy (85%), and C51 colon carcinoma, low cured which showed a poor response to therapy (30%). The combined treatment was exploited to determine the role of NK, DC and macrophages in WEHI-164 and C51 tumors. METHODS: The induced-immune responses were investigated by flow cytometry, intracellular immunostaining, chromium release cytotoxicity and FACS cell sorting. RESULTS: We found that 40h after L19TNFa/melphalan treatment in the WEHI-164, tumor-derived lymph nodes (TDLN) display an increased number of mature CD40+CD86+ DC, functional NK cells, CD4+ and CD8+ T cells as compared to LN of untreated mice. In the spleens of treated WEHI-164-bearing mice, we also observed TH1 cell polarization, CD8+ T cell activation and an increase in cytotoxic NK cells. With L19TNFa/melphalan treatment, increased mature DC were found among the immune cells infiltrating the tumors in conjunction with NK, CD4 and CD8 T cells, as compared to control mice early on after the combined treatment. Otherwise, in the TDLN of treated C51 tumor-bearing mice, neither a significant influx of mature DC, nor activation of NK cells was observed. In the spleens there was no activation of NK cells and a high MDSC population. Interestingly in both tumor models, a significant decrease of infiltrating M2-type macrophages was detected after the treatment. DISCUSSION AND CONCLUSIONS: These results strongly suggest that the success of L19TNFa/melphalan is related, in addition to the previous reported T cell responses, to the early activation and polarization of NK and DC. BIBLIOGRAPHY: L. Mortara, et al., Cancer Med. 2013. L. Mortara, et al., Eur. J. Immunol. 2007. L. Mortara, et al., Clin. Cancer Res. 2006.

Early triggering of natural killer and dendritic cell during antitumor therapeutic response induced by TNFa tumor vessel delivery and melphalan

ZANELLATO, SILVIA;MORTARA, LORENZO
2016

Abstract

PURPOSE: A systemic administration of L19mTNFa selectively targets the tumor vasculature, and in combination with melphalan is able to induce a long-lasting therapeutic response and immune T cell memory in two tumor mice models: WEHI-164 fibrosarcoma, that respond well to the therapy (85%), and C51 colon carcinoma, low cured which showed a poor response to therapy (30%). The combined treatment was exploited to determine the role of NK, DC and macrophages in WEHI-164 and C51 tumors. METHODS: The induced-immune responses were investigated by flow cytometry, intracellular immunostaining, chromium release cytotoxicity and FACS cell sorting. RESULTS: We found that 40h after L19TNFa/melphalan treatment in the WEHI-164, tumor-derived lymph nodes (TDLN) display an increased number of mature CD40+CD86+ DC, functional NK cells, CD4+ and CD8+ T cells as compared to LN of untreated mice. In the spleens of treated WEHI-164-bearing mice, we also observed TH1 cell polarization, CD8+ T cell activation and an increase in cytotoxic NK cells. With L19TNFa/melphalan treatment, increased mature DC were found among the immune cells infiltrating the tumors in conjunction with NK, CD4 and CD8 T cells, as compared to control mice early on after the combined treatment. Otherwise, in the TDLN of treated C51 tumor-bearing mice, neither a significant influx of mature DC, nor activation of NK cells was observed. In the spleens there was no activation of NK cells and a high MDSC population. Interestingly in both tumor models, a significant decrease of infiltrating M2-type macrophages was detected after the treatment. DISCUSSION AND CONCLUSIONS: These results strongly suggest that the success of L19TNFa/melphalan is related, in addition to the previous reported T cell responses, to the early activation and polarization of NK and DC. BIBLIOGRAPHY: L. Mortara, et al., Cancer Med. 2013. L. Mortara, et al., Eur. J. Immunol. 2007. L. Mortara, et al., Clin. Cancer Res. 2006.
Balza, E.; Zanellato, Silvia; Poggi, A.; Reverberi, D.; Rubartelli, A.; Mortara, Lorenzo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11383/2053046
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