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Theranostics 2020; 10(19):8619-8632. doi:10.7150/thno.45058 This issue Cite

Research Paper

C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation

Peipei Ding1, Ling Li1, Luying Li1, Xinyue Lv1, Danlei Zhou1, Qingkai Wang1, Jianfeng Chen1, Chaoqun Yang2, Enjie Xu2, Weixing Dai3, Xin Zhang1, Na Wang1, Qi Wang1, Wei Zhang1, Long Zhang1, Yuzhen Zhou1, Hongyu Gu1, Qunying Lei1,4, Xuhui Zhou2, Weiguo Hu1,4✉

1. Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
2. Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
3. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
4. Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.

✉ Corresponding author: Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, China. Tel.: +86 21 34777590; Fax: +86 21 64172585; E-mail address: weiguohuedu.cn (W.H.).

Citation:
Ding P, Li L, Li L, Lv X, Zhou D, Wang Q, Chen J, Yang C, Xu E, Dai W, Zhang X, Wang N, Wang Q, Zhang W, Zhang L, Zhou Y, Gu H, Lei Q, Zhou X, Hu W. C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation. Theranostics 2020; 10(19):8619-8632. doi:10.7150/thno.45058. https://www.thno.org/v10p8619.htm
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Abstract

Graphic abstract

Numerous factors have been claimed to play important roles in colorectal cancer (CRC) tumorigenesis, including myeloid-derived suppressor cells (MDSCs) and other immune cells, cytokines, and chemokines; however, the precise mechanisms of colorectal tumorigenesis remain elusive, and there is a lack of effective preventive treatments. Here, we investigated the role of complement system, a key regulator of immune surveillance and homeostasis, in colorectal tumorigenesis.

Methods: The prototypical CRC model was induced by combined administration of azoxymethane (AOM)/ dextran sulfate sodium (DSS) in Wild-type (WT), C3-, C5-, C5ar1-, and C5ar2-deficient mice. Using flow cytometry, immunohistochemical staining and multiplex bead assay, we profiled the immune cells, cytokines and chemokines. Bone marrow transplantation was employed to determine the contribution of immune cells in colorectal tumorigenesis. Further, we used C5aR1 antagonist PMX205 to investigate the protective role in colorectal tumorigenesis.

Results: Complement was extensively activated in inflamed tissues of AOM/DSS-induced murine CRC model, leading to multifaceted consequences. The deficiency of complement C5 or especially C5ar1, but not C3 almost completely prevented CRC tumorigenesis. C5a/C5aR1 signaling recruited MDSCs into the inflamed colorectum to impair CD8+ T cells, and modulated the production of critical cytokines and chemokines, thus initiating CRC. Moreover, the C5aR1 antagonist PMX205 strongly impeded colorectal tumorigenesis. Bone marrow transplantation further revealed that C5aR1 expression by immune cells was critical for colorectal tumorigenesis.

Conclusion: Our study identifies C5a/C5aR1 signaling as a vital immunomodulatory program in CRC tumorigenesis and suggests a feasible preventive strategy.

Keywords: Complement, C5aR1, colorectal tumorigenesis, immune modulation

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APA
Ding, P., Li, L., Li, L., Lv, X., Zhou, D., Wang, Q., Chen, J., Yang, C., Xu, E., Dai, W., Zhang, X., Wang, N., Wang, Q., Zhang, W., Zhang, L., Zhou, Y., Gu, H., Lei, Q., Zhou, X., Hu, W. (2020). C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation. Theranostics, 10(19), 8619-8632. https://doi.org/10.7150/thno.45058.

ACS
Ding, P.; Li, L.; Li, L.; Lv, X.; Zhou, D.; Wang, Q.; Chen, J.; Yang, C.; Xu, E.; Dai, W.; Zhang, X.; Wang, N.; Wang, Q.; Zhang, W.; Zhang, L.; Zhou, Y.; Gu, H.; Lei, Q.; Zhou, X.; Hu, W. C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation. Theranostics 2020, 10 (19), 8619-8632. DOI: 10.7150/thno.45058.

NLM
Ding P, Li L, Li L, Lv X, Zhou D, Wang Q, Chen J, Yang C, Xu E, Dai W, Zhang X, Wang N, Wang Q, Zhang W, Zhang L, Zhou Y, Gu H, Lei Q, Zhou X, Hu W. C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation. Theranostics 2020; 10(19):8619-8632. doi:10.7150/thno.45058. https://www.thno.org/v10p8619.htm

CSE
Ding P, Li L, Li L, Lv X, Zhou D, Wang Q, Chen J, Yang C, Xu E, Dai W, Zhang X, Wang N, Wang Q, Zhang W, Zhang L, Zhou Y, Gu H, Lei Q, Zhou X, Hu W. 2020. C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation. Theranostics. 10(19):8619-8632.

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