Oncolytic adenovirus promotes vascular normalization and nonclassical tertiary lymphoid structure formation through STING-mediated DC activation

Teng He; Zhixing Hao; Mingjie Lin; Zhongwei Xin; Yongyuan Chen; Wei Ouyang; Qi Yang; Xiaoke Chen; Hui Zhou; Wanying Zhang; Pin Wu; Feng Xu

doi:10.1080/2162402X.2022.2093054

Oncolytic adenovirus promotes vascular normalization and nonclassical tertiary lymphoid structure formation through STING-mediated DC activation

Oncoimmunology. 2022 Jul 1;11(1):2093054. doi: 10.1080/2162402X.2022.2093054. eCollection 2022.

Authors

Teng He¹, Zhixing Hao^{2

3}, Mingjie Lin^{2

3}, Zhongwei Xin^{2

3}, Yongyuan Chen^{2

3}, Wei Ouyang¹, Qi Yang⁴, Xiaoke Chen^{2

3}, Hui Zhou¹, Wanying Zhang¹, Pin Wu^{2

3}, Feng Xu¹

Affiliations

¹ Department of Infectious Diseases, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
² Department of Thoracic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
³ Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁴ Department of Emergency, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

Abstract

Inducing a full antitumor immune response in the tumor microenvironment (TME) is essential for successful cancer immunotherapy. Here, we report that an oncolytic adenovirus carrying mIL-15 (Ad-IL15) can effectively induce antitumor immune response and inhibit tumor growth in a mouse model of cancer. We found that Ad-IL15 facilitated the activation and infiltration of immune cells, including dendritic cells (DCs), T cells and natural killer (NK) cells, in the TME. Unexpectedly, we observed that Ad-IL15 also induced vascular normalization and tertiary lymphoid structure formation in the TME. Moreover, we demonstrated these Ad-IL15-induced changes in the TME were depended on the Ad-IL15-induced activation of the STING-TBK1-IRF3 pathway in DCs. Taken together, our findings suggest that Ad-IL15 is a candidate for cancer immunotherapy that promotes immune cell activation and infiltration, tumor vascular normalization and tertiary lymphoid structure formation in the TME.

Keywords: DC; Oncolytic virus; STING; tertiary lymphoid structure; vascular normalization.

MeSH terms

Adenoviridae / genetics
Adenoviridae / immunology
Animals
Cell Line, Tumor
Dendritic Cells / immunology
Immunotherapy
Interleukin-15* / administration & dosage
Interleukin-15* / immunology
Membrane Proteins* / immunology
Mice
Neoplasms / immunology
Neoplasms / therapy
Neoplasms / virology
Oncolytic Virotherapy
Tertiary Lymphoid Structures*

Substances

Interleukin-15
Membrane Proteins
Sting1 protein, mouse

Grants and funding

This work was supported by the Fundamental Research Funds for the Central Universities [2019QNA7025]; National Natural Science Foundation of China [81572800, 82073141, 81970004]; the Natural Science Foundation of Zhejiang Province [LR22H160006 and LY15H160041].