The immunosuppressive tumor environment is the major impediment to successful therapeutic vaccination in Neu transgenic mice.
We earlier showed that therapeutic vaccination of FVB/N mice with alphaviral replicon particles expressing rat neuET-VRP induced regression of established neu-expressing tumors. In this study, we evaluated the efficacy of neuET-VRPs in a tolerant mouse model using mice with transgenic expression of neu. Using the same approach that induced regression of 70 mm(2) tumors in FVB/N mice, we were unable to inhibit tumor growth in tolerant neu-N mice, despite showing neu-specific B-cell and T-cell responses post vaccination. As neu-N mice have a limited T-cell repertoire specific to neu, we hypothesized that the absence of these T cells led to differences in the vaccine response. However, transfer of neu-specific T cells from vaccinated FVB/N mice was not effective in inducing tumor regression, as these cells did not proliferate in the tumor-draining lymph node. Vaccination given with low-dose cyclophosphamide to deplete regulatory T cells delayed tumor growth but did not result in tumor regression. Finally, we showed that T cells given with vaccination were effective in inhibiting tumor growth, if administered with approaches to deplete myeloid-derived suppressor cells. Our data show that both central deletion of lymphocytes and peripheral immunosuppressive mechanisms are present in neu-N mice. However, the major impediment to successful vaccination is the peripheral tumor-induced immune suppression.
Burgents
Joseph E
JE
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
Moran
Timothy P
TP
West
Michelle L
ML
Davis
Nancy L
NL
Johnston
Robert E
RE
Serody
Jonathan S
JS
D019264:Adoptive Transfer; D000524:Alphavirus / Q000235:genetics* / Q000472:pathogenicity; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D007165:Immunosuppression Therapy; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012074:Remission Induction; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019139:Tumor Escape
D001324:Autoantigens; D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases; C483804:Erbb2 protein, rat