Checkpoint inhibitors led to clinical successes mainly in tumors with pre-existing anti-tumor T cells. In a preclinical model of HPV-E6-E7 expressing tumor with no spontaneous T cell infiltration, we test whether the induction of a recruitment of CD8+T cells by a vaccine would improve the efficacy of a therapeutic HPV vaccine.
Head and neck cancers are located at mucosal sites. We had previously shown that mucosal immunization is correlated with a strong protection against orthotopic head and neck cancer in both prophylactic and therapeutic settings, while systemic immunization was not (Sandoval F Sci Transl Med 2013). However, the mechanisms related to this protection remain unaddressed
We used a tumor model (TC1) expressing the E6-E7 protein from HPV16 grafted on a subcutaneous site or in the tongue (mucosal head and neck orthotopic site).
The therapeutic HPV vaccine selected was composed of the B subunit of Shiga toxin – a delivery vector targeting dendritic cells – fused to the E7 protein from HPV 16 (STxB-E7). This vaccine was admistered by the subcutaneous (systemic) route or the intranasal (mucosal) route alone or combined with anti-PD-L1.
We showed that when TC1 cells were grafted into mice, its growth was rapid and there was a poor infiltration with CD8+T cells. Administration of anti-PD-L1 mAb were inefficient to control the growth of this tumor. However, a synergy was observed when STxB-E7 was combined with anti-PD-L1. This synergy could be explained by the recruitment of intratumor CD8+T cells by the vaccine and the upregulation of PD-1 on these cells. In a second work, we tried to understand the mechanisms explaining the superiority of the intranasal route over the systemic route to control orthotopic head and neck cancers. Various experiments showed that resident memory CD8+T cells play a key role in the protection induced by the mucosal route of immunization. Finally, in human mucosal tumors, we confirmed the presence of Trm in situ and the improvement of survival in patients showing intratumoral Trm infiltration
Therapeutic vaccine may represent a rational combination with checkpoint blockade for tumors with no spontaneous T cell infiltration
Monitoring Trm may be used as a new surrogate biomarker of patient survival and may represent a new marker of vaccine efficacy for mucosal tumors.
Sandoval F et al Sci Transl Med 2013
Badoual C et al Cancer Res 2013
Nizard M et al Hum Vaccin Immunother 2014
Nizard M et al Clin Cancer Res 2015