One important goal of cancer immunotherapy is to prevent and treat tumor metastasis. We have previously reported the significant antitumor effect induced by the immunization with our human papillomavirus therapeutic protein-based vaccine (LALF-E7) without adjuvant and admixed with clinically relevant adjuvants in the subcutaneous TC-1 tumor challenge model. In the present study, we evaluated the efficacy of the above mentioned vaccine formulations in controlling the hematogenous spread of TC-1 tumor cells using a more tumourigenic clone named TC-1* and other intravenous injection site less stressful than the tail vein. We generated a lung metastasis model by injecting TC-1* cells into the retro-orbital venous sinus and this is the first study describing it. Also, this is the first study that demonstrates the efficacy of the immunization with LALF-E7 without adjuvant and admixed with VSSP or Al(OH) in controlling metastatic tumors increasing the survival of the mice. Our TC-1 lung metastasis model can be used to test the efficacy of other immunotherapeutic strategies based on E6/E7 antigens.

FoxL1+-Telocytes (TCFoxL1+) are subepithelial cells that form a network underneath the epithelium. We have shown that without inflammatory stress, mice with loss of function in the BMP signalling pathway in TCFoxL1+ (BmpR1aΔFoxL1+) initiated colonic neoplasia. Although TCFoxL1+ are modulated in IBD patients, their specific role in this pathogenesis remains unclear. Thus, we investigated how the loss of BMP signalling in TCFoxL1+ influences the severity of inflammation and fosters epithelial recovery after inflammatory stress. BmpR1a was genetically ablated in mouse colonic TCFoxL1+. Experimental colitis was performed using a DSS challenge followed by recovery steps to assess wound healing. Physical barrier properties, including mucus composition and glycosylation, were assessed by alcian blue staining, immunofluorescences and RT-qPCR. We found that BmpR1aΔFoxL1+ mice had impaired mucus quality, and upon exposure to inflammatory challenges, they had increased susceptibility to experimental colitis and delayed healing. In addition, defective BMP signalling in TCFoxL1+ altered the functionality of goblet cells, thereby affecting mucosal structure and promoting bacterial invasion. Following inflammatory stress, TCFoxL1+ with impaired BMP signalling lose their homing signal for optimal distribution along the epithelium, which is critical in tissue regeneration after injury. Overall, our findings revealed key roles of BMP signalling in TCFoxL1+ in IBD pathogenesis.

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Please cite this article as: Granadillo M, Alfonso AB, Vallespi MG, Batte A, Soria Y, Brown E, Limonta M, Prieto YC, Varas L, Torrens I, The LALF 32-51 peptide as component of HPV therapeutic vaccine circumvents the alum-mediated inhibition of IL-12 and promotes a Th1 response. AbstractAluminum-containing adjuvants (alum) continue to be the most widely used adjuvants. It is common knowledge that these adjuvants predominantly induce humoral immunity, but some reports also describe their role combined with IL-12 in the induction of a Th1 immune response.In this study we want to investigate if alum could be an adjuvant to be used as a component of a therapeutic vaccine that require the generation of cell-mediated immunity. To demonstrate this concept we selected the human papillomavirus (HPV) 16-transformed mouse TC-1 cells as model and the fusion protein LALF 32-51 -E7 as antigen. Our results suggest that LALF 32-51 -E7 combined with aluminum hydroxide adjuvant promotes a Th1 immune response and consequently an anti-tumor response in the TC-1 tumor model. These results could have important application in future clinical trials in women with low grade squamous intraepithelial neoplasia.

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