Abstract 2830: Mucosal imprinting of vaccine induced-CD8+T cells is crucial to inhibit mucosal tumors.
Authors: Sandoval Federico , Nizard Mevyn , Terme Magali , Badoual Cecile , Bureau Michel-Francis , Clement Olivier , Marcheteau Elie , Gey Alain , Dransart Estelle , Quintin-Colonna Françoise , Autret Gwenhael , Wu Tzyy-Choou , Fridman Wolf H. , Johannes Ludger , Tartour Eric 
Published: August 2014

Abstract
Although many human cancers are located in mucosal sites, most cancer vaccines are tested against subcutaneous tumors in preclinical models. The utility of preferentially inducing an anti-tumor immune response in the mucosal anatomic site of tumors has never been addressed. We therefore wondered whether mucosa-specific homing instructions to the immune system might influence mucosal tumor outgrowth. For this purpose, we set up original orthotopic models of head and neck and lung cancers monitored by magnetic resonance imaging or luciferase based in vivo optical imaging and vaccine based on a non replicative delivery system, the B subunit of Shiga toxin (STxB) as mucosal vector which has previously been shown to target antigen to dendritic cells. We showed that the growth of orthotopic head and neck or lung cancers expressing the E7 protein from HPV16 was only inhibited, when a cancer vaccine was delivered by the intranasal (i.n) mucosal and not the intramuscular (i.m) route. This anti-tumor effect was dependent on mucosal CD8+T cells as : i) Only a vaccine composed of STxB coupled to an E7 derived polypeptide (STxB-E7), but not the free E7 polypeptide elicited mucosal CD8+T cells. This mucosal induction of anti-E7 CD8+T cells, but not the systemic (spleen) specific anti-E7 CD8+T cells correlated with mucosal tumor protection. ii) A greater mucosal tumor infiltration of CD8+T cells was detected 7 days after tumor graft in mice that had been previously intranasally immunized with STxB-E7, than in mice vaccinated by the i.m. route. iii) CD8+T cell-depleted mice vaccinated with STxB-E7 by the i.n. route died before 20 days, whereas mice survived more than 6 months without CD8 depletion. As control, both routes of vaccine administration controlled the growth of subcutaneous tumors and elicited anti-E7 specific CD8+T cells in the spleen. To explain this finding, we demonstrated that only i.n. vaccination elicited mucosal specific CD8+T cells expressing the mucosal integrin CD49a. Blockade of CD49a decreased intratumoral CD8+T cell infiltration and the efficacy of cancer vaccine on mucosal tumor. We then showed that after intranasal vaccination, only dendritic cell from lung parenchyma, but not from spleen induced the expression of CD49a on co-cultured specific CD8+T cells. Tumor-infiltrating lymphocytes from human mucosal lung cancer also expressed CD49a at higher levels than TIL from non mucosal tumors, supporting the relevance and possible extrapolation of these results in humans. We thus identified a link between the route of vaccination and the induction of a mucosal homing program on induced CD8+T cells controlling their trafficking with a direct application on the efficacy of cancer vaccine to control mucosal tumors.
Citation Format: Federico Sandoval, Mevyn Nizard, Magali Terme, Cecile Badoual, Michel-Francis Bureau, Olivier Clement, Elie Marcheteau, Alain Gey, Estelle Dransart, Françoise Quintin-Colonna, Gwenhael Autret, Tzyy-Choou Wu, Wolf H. Fridman, Ludger Johannes, Eric Tartour. Mucosal imprinting of vaccine induced-CD8+T cells is crucial to inhibit mucosal tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2830. doi:10.1158/1538-7445.AM2013-2830