Introduction: Among the innate cells involved in the rejection and memory process, DCs appear the major APCs able to convey to tumor-specific T cells effective signals for early antigen recognition and T-cell activation. Interestingly, it has also been shown that DCs can interact with NK cells via a cooperative cross-talk that leads to activation of each other and to development of immune TH1 cells and activation of CTL effector response. We previously demonstrated that a single systemic administration of L19mTNFa selectively targets the tumor vasculature, and in combination with melphalan is able to induce a long-lasting therapeutic T cell immune response in two tumor mouse 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%). In the present study we wanted to investigate the role of NK, DC and macrophages during the combined treatment in WEHI-164 and C51 tumors. Material and method: The induced-immune responses were investigated in spleens, lymph nodes and tumor-infiltrated lymphocytes by flow cytometry, intracellular immunostaining, chromium release cytotoxicity and FACS cell sorting. Results and discussion: 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+ DCs, 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 NKs, 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. Conclusion: 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 cells and DCs.

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

ZANELLATO, SILVIA;MORTARA, LORENZO
2016

Abstract

Introduction: Among the innate cells involved in the rejection and memory process, DCs appear the major APCs able to convey to tumor-specific T cells effective signals for early antigen recognition and T-cell activation. Interestingly, it has also been shown that DCs can interact with NK cells via a cooperative cross-talk that leads to activation of each other and to development of immune TH1 cells and activation of CTL effector response. We previously demonstrated that a single systemic administration of L19mTNFa selectively targets the tumor vasculature, and in combination with melphalan is able to induce a long-lasting therapeutic T cell immune response in two tumor mouse 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%). In the present study we wanted to investigate the role of NK, DC and macrophages during the combined treatment in WEHI-164 and C51 tumors. Material and method: The induced-immune responses were investigated in spleens, lymph nodes and tumor-infiltrated lymphocytes by flow cytometry, intracellular immunostaining, chromium release cytotoxicity and FACS cell sorting. Results and discussion: 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+ DCs, 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 NKs, 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. Conclusion: 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 cells and DCs.
Zanellato, Silvia; Balza, E.; Poggi, A.; Reverberi, D.; Rubartelli, A.; Mortara, Lorenzo
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11383/2053028
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact