Targeting complement C5a to improve radiotherapy sensitivity in non-small cell lung cancer

Meng Yuan; Chenlin Wang; Yanan Wu; Lili Qiao; Guodong Deng; Ning Liang; Fangjie Chen; Li Liu; Yanfei Chen; Yunxin Yang; Hang Wang; Tong Liu; Xiaofan Yang; Yingying Zhang; Yajuan Lv; Rafal Suwinski; Pingping Hu; Yan Zhang; Jiandong Zhang

doi:10.21037/tlcr-23-258

Targeting complement C5a to improve radiotherapy sensitivity in non-small cell lung cancer

Transl Lung Cancer Res. 2023 May 31;12(5):1093-1107. doi: 10.21037/tlcr-23-258. Epub 2023 May 29.

Authors

Meng Yuan^#¹, Chenlin Wang^#^{2

3}, Yanan Wu^{3

4}, Lili Qiao³, Guodong Deng³, Ning Liang³, Fangjie Chen³, Li Liu^{3

5

6}, Yanfei Chen^{3

4}, Yunxin Yang^{3

5

6}, Hang Wang^{3

4}, Tong Liu^{3

5

6}, Xiaofan Yang⁷, Yingying Zhang³, Yajuan Lv³, Rafal Suwinski⁸, Pingping Hu³, Yan Zhang^{3

6}, Jiandong Zhang³

Affiliations

¹ Department of Oncology, Shandong Provincial Qianfoshan Hospital, Weifang Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China.
² School of Clinical Medicine, Weifang Medical University, Weifang, China.
³ Department of Oncology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China.
⁴ Department of Oncology, Shandong First Medical University, Jinan, China.
⁵ Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
⁶ Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁷ School of Clinical Medicine, Jining Medical University, Jining, China.
⁸ Radiotherapy and Chemotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland.

^# Contributed equally.

Abstract

Background: Tumor local and distant relapse recurrence after radiotherapy (RT) is one of the critical factors leading to poor prognosis. The effective antitumor effects of RT are dependent upon the participation of innate and adaptive components of the immune system. C5a/C5aR1 signaling can regulate antitumor immune effect in the tumor microenvironment (TME). Thus, exploring the changes and mechanism in the TME induced by RT-mediated complement activation may provide a novel perspective for reversing radioresistance.

Methods: First, fractionated radiation of 8 Gy ×3 fractions were targeted at Lewis lung carcinoma (LLC) tumor-bearing female mice to measure the infiltration of CD8⁺ T cell and analyze the RNA sequencing (RNA-seq) in RT-recruited CD8⁺ T cells. Second, tumor growth was measured in LLC tumor-bearing mice treated with RT either with or without C5aR1 inhibitor to clarify the antitumor effect of RT combined with C5aR1 inhibitor. Third, we detected the expression of C5a/C5aR1 and their signaling pathways on radiated tumor tissues. Furthermore, we investigated the expression of C5a in tumor cells at different time points after different doses of RT.

Results: In our system, RT induced the increased infiltration of CD8⁺ T cells and local activation of complement C5a/C5aR. Concurrent administration of RT and blocking of C5aR improved radiosensitivity and tumor-specific immune response, which was reflected by high C5aR expression in CD8⁺ T cells. The AKT/NF-κB pathway was found to be an important signaling pathway in C5a/C5aR axis mediation by RT.

Conclusions: RT promotes the release of C5a from tumor cells and leads to up-regulation of C5aR1 expression via the AKT/NF-κB pathway. Inhibition of the combination of complement C5a and C5aR could improve RT sensitivity. Our work provides evidence that the combination of RT and C5aR blockade opens a new window of opportunity to promote anti-tumor therapeutic effects in lung cancer.

Keywords: Radiotherapy (RT); complement C5a; non-small cell lung cancer (NSCLC); radioresistance; radiosensitivity.