Induction of systemic immune responses and reversion of immunosuppression in the tumor microenvironment by a therapeutic vaccine for cervical cancer.

Abstract

Cervical cancer is the most common malignant tumor of the genital tract in females worldwide. Persistent human papillomavirus (HPV) infection is closely associated with the occurrence of cervical cancer. No licensed therapeutic HPV vaccines for cervical cancer are currently available. In our previous study, we demonstrated that the vaccine containing the HPV16 E7 43-77 peptide and the adjuvant unmethylated cytosine-phosphate-guanosine oligodeoxynucleotide elicited significant prophylactic and therapeutic effects on cervical cancer. In the current study, we comprehensively evaluated the effect of the vaccine on systemic immune responses and the tumor microenvironment (TME) in a mouse model of cervical cancer. The results showed that the administration of the vaccine induced a significant increase in splenic IFN-γ-producing CD4 and CD8 T cells as well as tumor infiltrating CD4 and CD8 T cells. Moreover, marked decreases in splenic MDSCs and Tregs as well as intratumoral MDSCs, Tregs and type 2-polarized tumor-associated macrophages were observed in the vaccine group. The profile of cytokines, chemokines and matrix metalloproteinases (MMPs) in the TME revealed significantly increased expression of IL-2, IL-12, TNF-α, IFN-γ, CCL-20, CXCL-9, CXCL-10 and CXCL-14 and decreased expression of IL-6, IL-10, TGF-β, CCL-2, CCL-3, CCL-5, CXCL-8, MMP-2, MMP-9 and VEGF in the vaccine group. The expression of the cell proliferation indicator Ki67, apoptosis regulatory protein p53 and angiogenesis marker CD31 was significantly decreased in the vaccine group. In conclusion, the vaccine reversed tolerogenic systemic and local TME immunosuppression and induced robust antitumor immune responses, which resulted in the inhibition of established implanted tumors.