PMID- 17479109
OWN - NLM
STAT- MEDLINE
DCOM- 20070912
LR  - 20211203
IS  - 0929-1903 (Print)
IS  - 0929-1903 (Linking)
VI  - 14
IP  - 7
DP  - 2007 Jul
TI  - Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated 
      TNF-alpha gene transfection counteract immunosuppressive interleukin-10-secreting 
      lung metastasis and solid tumors.
PG  - 661-75
AB  - T-cell suppression derived from tumor-secreted immunosuppressive interleukin 
      (IL)-10 becomes a major barrier to CD8+ T-cell immunotherapy of tumors. Tumor 
      necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine capable of 
      activating T and dendritic cells (DCs) and counteracting IL-10-mediated DC 
      inhibition and regulatory T-cell-mediated immune suppression. In this study, we 
      constructed a recombinant adenovirus (MF)AdVTNF with fiber-gene modified by RGD 
      insertion into the viral knob's H1 loop and a melanoma cell line B16(OVA/IL-10) 
      engineered to express ovalbumin (OVA) and to secrete IL-10 (2.2 ng/ml/10(6) 
      cells/24 h). We transfected OVA-specific CD8+ T cells with (MF)AdVTNF, and found 
      a fivefold increase in transgene human TNF-alpha secretion (4.3 ng/ml/10(6) 
      cells/24 h) by the engineered CD8+ T(TNF) cells transfected with (MF)AdVTNF, 
      compared to that (0.8 ng/ml/10(6) cells/24 h) by CD8+ T cells transfected with 
      the original AdVTNF without viral fiber modification. The engineered CD8+ T(TNF) 
      cells exhibited enhanced cytotoxicity and elongated survival in vivo after 
      adoptive transfer. TNF-alpha derived from both the donor CD8+ T cells and the 
      host cells plays an important role in donor CD8+ T-cell survival in vivo after 
      adoptive transfer. We also demonstrated that the transfected B16(OVA/IL-10) tumor 
      cells secreting IL-10 are more resistant to in vivo CD8+ T-cell therapy than the 
      original B16(OVA) tumor cells without IL-10 expression. Interestingly, the 
      engineered CD8+ T(TNF) cells secreting transgene-coded TNF-alpha, but not the 
      control CD8+ T(control) cells without any transgene expression eradicated 
      IL-10-secreting 12-day lung micrometastasis in all 10/10 mice and IL-10-secreting 
      solid tumors ( approximately 5 mm in diameter) in 6/10 mice. Transfer of the 
      engineered CD8+ T(TNF) cells further induced both donor- and host-derived memory 
      CD8+ T cells, leading to a stronger long-term antitumor immunity against the 
      IL-10-secreting B16(OVA/IL-10) tumor cell challenges. Therefore, CD8+ T cells 
      engineered to secrete TNF-alpha may be useful when designing strategies for 
      adoptive T-cell therapy of solid tumors.
FAU - Ye, Z
AU  - Ye Z
AD  - Research Unit, Health Research Division, Saskatchewan Cancer Agency, Saskatoon, 
      Saskatchewan, Canada.
FAU - Shi, M
AU  - Shi M
FAU - Chan, T
AU  - Chan T
FAU - Sas, S
AU  - Sas S
FAU - Xu, S
AU  - Xu S
FAU - Xiang, J
AU  - Xiang J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070504
PL  - England
TA  - Cancer Gene Ther
JT  - Cancer gene therapy
JID - 9432230
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 130068-27-8 (Interleukin-10)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Humans
MH  - Immunologic Memory
MH  - Immunosuppression Therapy
MH  - Interleukin-10/*genetics
MH  - Lung Neoplasms/immunology/*secondary
MH  - Melanoma/*immunology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neoplasms/*immunology
MH  - T-Lymphocytes, Cytotoxic/*immunology
MH  - Thymoma/immunology
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/*genetics
EDAT- 2007/05/05 09:00
MHDA- 2007/09/13 09:00
CRDT- 2007/05/05 09:00
PHST- 2007/05/05 09:00 [pubmed]
PHST- 2007/09/13 09:00 [medline]
PHST- 2007/05/05 09:00 [entrez]
AID - 7701039 [pii]
AID - 10.1038/sj.cgt.7701039 [doi]
PST - ppublish
SO  - Cancer Gene Ther. 2007 Jul;14(7):661-75. doi: 10.1038/sj.cgt.7701039. Epub 2007 
      May 4.