Abstract 5388: Local mucosal CD8+T cell response is required to inhibit the growth of orthotopic head and neck and lung cancers
Authors: Sandoval Federico , Terme Magali , Badoual Cecile , Nizard Mevyn , Bureau Michel Francis , Freyburger Ludovic , Clement Olivier , Gey Alain , Marcheteau Elie , Fraisse Guillaume , Merillon Nathalie , Dransart Estelle , Quintin-Colonna Françoise , Wu Tzyy-Choou , Fridman Wolf H. , Johannes Ludger , Tartour Eric 
Published: August 2012

Tumors may be located at mucosal or non-mucosal sites. However, the clinical benefit of preferentially inducing an anti-tumor immune response in the anatomic site of tumors has never been addressed. We set up orthotopic models of head and neck and lung cancers to compare the systemic and local anti-tumor immune response after administration of a cancer vaccine by mucosal and systemic routes. We also selected a non replicative delivery system, the B subunit of Shiga toxin (STxB), as a mucosal vector able to target dendritic cells. We show that intranasal immunization of mice with STxB based vaccine is the best route to elicit polyfunctional specific CD8+T cells in cervical and mediastinal lymph node than the use of non vectorized antigen or the intramuscular route. In line with these results, nasal mucosal administration of a model tumor antigen (E7 polypeptide from HPV 16) targeted to dendritic cells by STxB is more efficient to inhibit the growth of established orthotopic head and neck and lung cancers expressing the E7 antigen, than the administration of non vectorized antigen or the use of intramuscular route. A higher infiltration of CD8+T cells was detected 7 days after tumor graft, when mice were previously intranasally immunized with STxB-E7, than in mice vaccinated by the intramuscular route. Specific anti-E7 CD8+T cell tumor infiltration, was only observed after nasal immunization. Indeed, depletion of CD8+T cells inhibited the clinical efficiency of tumor vaccine demonstrating their role in tumor protection. In contrast, both routes completely controlled the growth of a subcutaneously E7 expressing tumor, which correlated with a similar induction of anti-E7 CD8+T cells in the spleen. Analysis of Integrin and chemokine receptor expression on tetramere positive cells showed that intranasal immunization induced higher levels of CD103 on T cells in bronchoalveolar lavage than intramuscular immunization with the same vaccine. This study emphasizes the need to elicit a potent anti-tumor response at the anatomic site of tumor and not just in the systemic compartment to induce tumor regression. This was achieved by i) administration of the vaccine by the intranasal route which was efficient in inducing CD8+T cells response at both locoregional and systemic sites allowing the control of both mucosal and non mucosal tumors. ii) The targeting of antigen to dendritic cells by STxB. This study is relevant to humans, as 30% of head and neck cancers express HPV16. Our results support the development of STxB-E7 vaccine administered by the i.n. route for the treatment of these HPV associated head and neck cancers. More generally, this study provides direct evidence for the compartmentalization of tumor immunity, a critical finding for the design of better cancer vaccines.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5388. doi:1538-7445.AM2012-5388