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

Author(s)

Pinho, Mariana Pereira ^[1] ; Sundarasetty, Bala Sai ^[2] ; Bergami-Santos, Patricia Cruz ^[1] ; Steponavicius-Cruz, Karen ^[1] ; Ferreira, Adilson Kleber ^[1] ; Stripecke, Renata ^[2] ; Barbuto, Jose Alexandre M. ^{[1, 3]}

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Av Prof Lineu Prestes 1730, BR-05508000 Sao Paulo, SP - Brazil

^[2] Hannover Med Sch, Rebirth Excellence Cluster & Dept Hematol Hemosta, Hannover - Germany

^[3] Univ Sao Paulo, NUCEL NETCEM, Cell & Mol Therapy Ctr, Sao Paulo - Brazil

• Document type: Journal article
• Source: CYTOTHERAPY; v. 18, n. 4, p. 570-580, APR 2016.
• Web of Science Citations: 6

Abstract

Background aims. 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)-gamma 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-gamma 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-specificT-cell expansion and were the only cells able to induce IFN-gamma-producing antigen-specific T cells. Thus, these data offer further support for cancer immunotherapeutic approaches using DC-tumor cell hybrids. (AU)

• FAPESP's process: 13/26044-4 - In vitro sensitization of T lymphocytes for analysis of the immunostimulation ability of dendritic-tumor cell hybrids
• Grantee: Mariana Pereira Pinho
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 09/54599-5 - Dendritic cells: integrative elements of the immune system - an applied approach
• Grantee: Jose Alexandre Marzagão Barbuto
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/10939-0 - Antigenic enrichment of tumor cell lines: a strategy for personalized immunotherapeutic approaches
• Grantee: Mariana Pereira Pinho
• Support Opportunities: Scholarships in Brazil - Master