![]() Comparing young wt to young E7-tg mice or older wt to older E7-tg mice vaccinated with AdE7 showed significant differences (P values <0.002). Comparing mice matched for strain (E7-tg versus wt mice), tissue (spleen, blood, or thyroid), and age (young versus older) groups immunized with AdE7 versus AdgDE7 showed significant differences in all comparisons with P values 0.1). Significance of differences between groups was calculated by one-tailed Student t-test. Experiments were conducted with 3–10 mice per group. Graphs c1–3 show frequencies of E7-tet+CD44highCD8+ cells over total CD8+ cells, and c4 shows numbers of E7-tet+CD44highCD8+ cells per thyroid gland. Fourteen days later (1) spleens, (2) PBMCs isolated from wt and E7-tg mice and lymphocytes isolated from (3, 4) thyroid glands of E7-tg mice were analyzed by staining with the E7-tetramer. (c) Young (2-month-old) and older (8- to 10-month-old) wt C57Bl/6 and E7-tg mice were intramuscularly (i.m.) immunized with 5 × 1010 virus particles of E1-deleted Ad vectors carrying either E7 (black bars) or gDE7 (gray bars). For HVEM-KO mice comparing responses to AdE7 to those of AdgDE7 P value was 0.43 for wt C57Bl/6 mice the difference between these two vaccine groups was statistically significant (P = 0.0004). Significance of differences between the groups was determined by one-tailed Student t-tests. PBMCs from C57Bl/6 mice were tested 3 weeks after immunization. HVEM-KO mice were bled 4 weeks later and frequencies of E7-specific CD8+ T cells were determined by intracellular cytokine staining for interferon-γ. (b) HVEM-KO mice or wt C57Bl/6 mice were vaccinated with AdE7 (black squares) or AdgDE7 (open squares). Graphs shows intensity for the HVEM stain on CD3+ cells from wt C57Bl/6 mice (dark gray) and HVEM-KO mice (light gray) over % of maximal events. (a) Peripheral blood mononuclear cells (PBMCs) of herpes virus entry mediator knockout (HVEM-KO) mice or wild-type (wt) C57Bl/6 mice were stained with antibodies to CD3 and HVEM. Vaccine-induced E7-specific CD8+ T-cell responses. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors. ![]() Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models.
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