Efficient eradication of subcutaneous but not of autochthonous gastric tumors by adoptive T cell transfer in an SV40 T antigen mouse model.
In stomach cancer, there is a need for new therapeutic strategies, in particular for the treatment of unresectable tumors and micrometastases. We investigated the efficacy of immunotherapy in an autochthonous model of gastric cancer, the CEA424-SV40 T Ag (TAg) transgenic mice. Treatment efficacy against both the autochthonous tumors and s.c. tumors induced by the derived cell line mGC3 were assessed. In wild-type mice, a dendritic cell vaccine loaded with irradiated tumor cells combined with CpG oligonucleotides induced efficient cytotoxic T cell and memory responses against mGC3 s.c. tumors. In contrast, neither s.c. nor autochthonous tumors responded to vaccination in CEA424-SV40 TAg mice, indicating tolerance to the SV40 TAg. To examine whether tumors in these mice were principally accessible to immunotherapy, splenocytes from immune wild-type mice were adoptively transferred into CEA424-SV40 TAg transgenic mice. Treated mice showed complete regression of the s.c. tumors associated with intratumoral infiltrates of CD8 and CD4 T cells. In contrast, the autochthonous gastric tumors in the same mice were poorly infiltrated and did not regress. Thus, even in the presence of an active anti-tumoral T cell response, autochthonous gastric tumors do not respond to immunotherapy. This is the first comparison of the efficacy of adoptive T cell transfer between transplanted s.c. tumors and autochthonous tumors in the same animals. Our results suggest that in gastric cancer patients, even a strong anti-tumor T cell response will not efficiently penetrate the tumor in the absence of additional therapeutic strategies targeting the tumor microenvironment.
Bourquin
Carole
C
Division of Clinical Pharmacology, Center of Integrated Protein Science Munich, Germany. carole.bourquin@med.lmu.de
von der Borch
Philip
P
Zoglmeier
Christine
C
Anz
David
D
Sandholzer
Nadja
N
Suhartha
Nina
N
Wurzenberger
Cornelia
C
Denzel
Angela
A
Kammerer
Robert
R
Zimmermann
Wolfgang
W
Endres
Stefan
S
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D018899:CpG Islands / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009841:Oligonucleotides / Q000008:administration & dosage / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014611:Vaccination
D000952:Antigens, Polyomavirus Transforming; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D009841:Oligonucleotides; D011993:Recombinant Fusion Proteins