Dendritic-tumor cell hybrids induce tumor-specific immune responses more effectively than the simple mixture of dendritic and tumor cells

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• 作者：Mariana Pereira Pinho¹ ; Bala Sai Sundarasetty² ; Patricia Cruz Bergami-Santos¹ ; Karen Steponavicius-Cruz¹ ; Adilson Kleber Ferreira¹ ; Renata Stripecke² ; José ; Alexandre M. Barbuto¹ ; ³ ; ^{jbarbuto@icb.usp.br" class="auth_mail" title="E-mail the corresponding author}
• 关键词：cancer vaccines ; cell fusion ; dendritic cells ; hybrid cells ; immunotherapy
• 刊名：Cytotherapy
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：18
• 期：4
• 页码：570-580
• 全文大小：1479 K

文摘

Dendritic cell (DC)-tumor cell hybrids have been used clinically in cancer immunotherapy, but their advantage over the simple mixture of tumor cells and DCs is still a matter of controversy. In this study, we compared DC-tumor cell hybrids with the non-fused mixture of DC and tumor cells directly in their ability to induce a specific immune response.

Methods

Hybrids were obtained by electrofusion of tumor cells and monocyte-derived DCs. Cell phenotype was evaluated by flow cytometry and antigen-presenting ability by co-culture with syngeneic T cells followed by tetramer analysis and interferon (IFN)-γ ELISPOT.

Results

Less than half the cells in the mixture expressed DC co-stimulatory molecules. Furthermore, DCs in the mixture had significantly lower expression of MHC class I molecules than DCs in the fusion. Conversely, nearly all CD11c⁺Her2/neu⁺ hybrids expressed CD80, CD86, CD83, HLA-DR and MHC class I from both tumor cells and DCs. Using tumor cells constitutively expressing a cytomegalovirus (CMV) antigen, we show that expansion of CMV-specific cytotoxic T lymphocytes (CTLs) restricted by DCs' MHC class I molecules was higher when DC-tumor hybrids were the stimulators. Furthermore, only hybrids stimulated CTLs to produce IFN-γ in response to CMV-positive target cells.

Conclusions

These data show the superiority of DC-tumor cell hybrids over their simple mixture as T-cell stimulators. Hybrids expressed more co-stimulatory and MHC molecules, induced higher antigen-specific T-cell expansion and were the only cells able to induce IFN-γ–producing antigen-specific T cells. Thus, these data offer further support for cancer immunotherapeutic approaches using DC-tumor cell hybrids.