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

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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.

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Abbreviations

ANOVA:

Analysis of variance

CCL:

CC-chemokine ligand

CXCL:

CXC-chemokine ligand

CTLs:

Cytotoxic T lymphocytes

CpG ODN:

Unmethylated cytosine-phosphate-guanosine oligodeoxynucleotide

DCs:

Dendritic cells

H&E:

Hematoxylin and eosin

HPV:

Human papillomavirus

M1-TAMs:

Type 1-polarized tumor-associated macrophages

M2-TAMs:

Type 2-polarized tumor-associated macrophages

MMPs:

Matrix metalloproteinases

MDSCs:

Myeloid-derived suppressor cells

MVD:

Microvessel density

M-MDSC:

Monocytic MDSC

NK:

Natural killer

PMN-MDSC:

Polymorphonuclear MDSC

qRT-PCR:

Quantitative real-time reverse transcription polymerase chain reaction

Tregs:

Regulatory T cells

TME:

Tumor microenvironment

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81472439), and the Natural Science Foundation of Liaoning Province (No. 20180550760).

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Authors and Affiliations

  1. Department of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China

    Yuxin Che, Yang Yang, Jinguo Suo & Xuelian Wang

  2. School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China

    Yujing An

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  1. Yuxin Che
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  2. Yang Yang
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  3. Jinguo Suo
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  4. Yujing An
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Contributions

XW, YC and YY designed the experiments; YC, YY, JS and YA carried out experiments; YC analyzed the data and wrote the manuscript.

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Correspondence to Xuelian Wang.

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The study was approved by the Institutional Animal Care and Use Committee of the China Medical University.

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Fig. 1

Effect of the vaccine on systemic immune responses. The vaccine increased the percentage of a,b IFN-γ-producing CD4 and c,d IFN-γ-producing CD8 T cells; and decreased the percentage of e,f MDSCs and g,h Tregs in the spleen. Representative scatter plots from one mouse (out of three mice) showing a IFN-γ-producing CD4 T cells, c IFN-γ-producing CD8 T cells, e MDSCs and g Tregs. Flow cytometry data showing splenic IFN-γ-producing CD4 and CD8 T cells, MDSCs and Tregs is represented as a bar graph expressed as b %CD4+IFN-γ+ cells, d %CD8+IFN-γ+ cells, f %CD11b+Gr-1+ cells and h %CD4+Foxp3+ cells. The data are depicted as the mean±SD (n=3). The significance of the data was evaluated by one-way ANOVA followed by Tukey’s multiple comparison test (*p<0.05, **p<0.01).

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Che, Y., Yang, Y., Suo, J. et al. Induction of systemic immune responses and reversion of immunosuppression in the tumor microenvironment by a therapeutic vaccine for cervical cancer. Cancer Immunol Immunother 69, 2651–2664 (2020). https://doi.org/10.1007/s00262-020-02651-3

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