Early triggering of natural killer and dendritic cell during antitumor therapeutic response induced by TNFa tumor vessel delivery and melphalan
Abstract
Publication Date:
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.
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.
Iris type:
Abstract (in Volume)
Keywords:
Natural killer cells, dendritic cell, antitumor therapeutic response, TNFa, targeting delivery, melphalan
List of contributors:
Balza, E.; Zanellato, Silvia; Poggi, A.; Reverberi, D.; Rubartelli, A.; Mortara, Lorenzo
Book title:
Xth National Conference of the Italian Society of Immunology, Clinical Immunology and Allergology (SIICA)