Intravaginal live attenuated Salmonella increase local antitumor vaccine-specific CD8+ T cells - PubMed (original) (raw)

Intravaginal live attenuated Salmonella increase local antitumor vaccine-specific CD8+ T cells

Loane Decrausaz et al. Oncoimmunology. 2013.

Abstract

We have recently reported that the intravaginal instillation of synthetic Toll-like receptor 3 (TLR3) or TLR9 agonists after a subcutaneous vaccination against human papillomavirus E7 highly increases (~5-fold) the number of vaccine-specific CD8+ T cells in the genital mucosa of mice, without affecting E7-specific systemic responses. Here, we show that the instillation of live attenuated Salmonella enterica serovar Typhimurium similarly, though more efficiently (~15- fold), increases both E7-specific and total CD8+ T cells in the genital mucosa. Cancer immunotherapeutic strategies combining vaccination with local immunostimulation with live bacteria deserve further investigations.

Keywords: CD8+ T cells; bacterial immunostimulant; genital mucosa; human papillomavirus; vaccination.

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Figures

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Figure 1. IVAG PhoPc or AroA bacteria administered after E7 immunization increased E7-specific effector CD8+ T cells in the cervix-vagina. Groups of mice were s.c. immunized with 50 μg E71–98 + 10 μg CpG + 0.4 μg Escherichia coli heat labile toxin (E7 vaccine) and 5 days later instilled in vagina with PBS, 100 μg CpG, ~5x 108 CFU of PhoPc, AroA or heat-killed (HK) AroA bacteria. Mice were sacrificed three days later and cells recovered from the cervix-vagina were analyzed by ex vivo IFNγ ELISPOT as previously described. The numbers of E749–57 specific IFNγ-secreting cells/105 cells are indicated. Horizontal bars represent mean responses. Significant differences are indicated by *p < 0.05, **p < 0.01 and ***p < 0.001 following one-way ANOVA and Tukey’s post test (GraphPad Prism 5).

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Figure 2. Bacterial expression of E7 modestly influenced the fold-increase of E7-specific CD8+ T cells in the cervix-vagina upon intravaginal instillation. (A) The plasmid pFSnsd-kan3-mtHsp70HPV16E7Δ21–26E6Δ118−122 contains within the _Nco_I and _Hind_III restrictions sites, instead of L1S, a sequence encompassing the full lenght Mycobacterium tuberculosis (mt) heat-shock protein 70 (Hsp70) open reading frame (ORF) fused to the E7 ORF deleted from residues 21 to 26 and the E6 ORF deleted from residues 118–122. (B). Expression of the fusion protein (~100 KDa) in PhoPc bacterial lysates (lane HspE7E6) is detected with polyclonal anti-E7 and anti-E6 antibodies (kindly provided by Dr. John Schiller, NCI, Bethesda, USA) as well as with a monoclonal anti-mtHsp70 antibody (HyTest Ltd, Turku, Finland). For comparison, E7 and E6 only are detected in bacterial lysates from PhoPc cells expressing an E7-E6 fusion without Hsp70 (~32 KDa). (C) Mice s.c. immunized with the adjuvanted E7 vaccine and receiving 5 d later intravaginal PBS, CpG, PhoPc or PhoPcE7 cells were sacrificed at day 9 (left) or at day 15 (right) and cells recovered from cervix-vagina were analyzed by ex vivo IFNγ ELISPOT. The numbers of E749–57- specific IFNγ-secreting cells/105 cells are indicated. Horizontal bars represent mean responses. Significant differences are indicated by *p < 0.05 and *** p < 0.001 following one-way ANOVA and Tukey’s post test (GraphPad Prism 5).

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