Premium
Influence of drug‐induced apoptotic death on processing and presentation of tumor antigens by dendritic cells
Author(s) -
Buttiglieri Stefano,
Galetto Alessandra,
Forno Sarah,
De Andrea Marco,
Matera Lina
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11243
Subject(s) - propidium iodide , apoptosis , immunogenic cell death , programmed cell death , cancer research , biology , annexin , tumor necrosis factor alpha , microbiology and biotechnology , antigen , elispot , dendritic cell , medicine , immunology , t cell , flow cytometry , immune system , biochemistry
Abstract Here we have studied the effects of apoptotic cell death induced by chemotherapic agents on tumor phagocytosis by dendritic cells (DC) and presentation of the relevant antigen to T lymphocytes. Annexin‐V‐FITC (Ann‐V) and propidium iodide (PI) staining was used to assess early apoptotic (Ann‐V + /PI − ) vs. late apoptotic/secondary necrotic (Ann‐V + /PI + ) death after a 24 hr observation of untreated and drug‐treated gastric carcinoma cells. After treatments, the HLA‐A*0201 + tumor cell line KATO III was exposed for 24 hr to allogeneic, HLA‐related GM‐CSF, IL‐4‐driven immature ( i ) DC. Tumor‐loaded i DC were tested for IL‐12 release in an ELISA assay, incubated with the DC‐maturating factor TNF‐α and used as stimulators for autologous T lymphocytes. Generation of antitumor T response against KATO cells was evaluated in an anti‐MHC class I MAb‐blocked Interferon‐γ ELISPOT assay. After treatment with Cis‐platin ( cis ), all dying cells were in early apoptosis, whereas secondary necrosis was the prevalent death pattern observed after epirubicin ( epi ) and doxorubicin ( doxo ). Doxo and epi increased tumor expression of heat shock protein ( hsp ) 70 and uptake of tumor cell components by DC, whereas cis treatment had no effect on hsp70 and was associated with poor tumor uptake by DC. Significant upmodulation of IL‐12 was observed by DC that had taken up the doxo‐ and epi ‐treated tumors ( p < 0.005 and p < 0.01, respectively). Increased IFN‐γ release was also observed after stimulation of T lymphocytes with DC loaded with doxo‐ and epi ‐treated ( p < 0.02 and p < 0.005, respectively) but not with cis ‐treated DC. These data show that the products of early apoptosis cannot efficiently cross‐activate MHC class I‐restricted anti‐tumor lymphocytes even in the presence of DC maturating factors, whereas secondary necrosis is associated with robust T cell response. © 2003 Wiley‐Liss, Inc.