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Theranostics 2023; 13(5):1649-1668. doi:10.7150/thno.80483 This issue Cite

Research Paper

Alarmin IL-33 orchestrates antitumoral T cell responses to enhance sensitivity to 5-fluorouracil in colorectal cancer

Mengjia Song1,2#, Jieying Yang1,3#, Muping Di1,3#, Ye Hong1,2#, Qiuzhong Pan1,3, Yufei Du1,3, Tong Xiang1,3, Juan Liu1,2,4, Yan Tang1,3, Qijing Wang1,3, Yongqiang Li1,3, Jia He1,3, Hao Chen1,3, Jingjing Zhao1,3, Desheng Weng1,3, Yizhuo Zhang1,2✉, Jian-Chuan Xia1,3✉

1. Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
2. Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
3. Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
4. Department of Pediatric Oncology, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
# These authors contributed equally to this work.

✉ Corresponding authors: Jian-Chuan Xia (xiajchsysu.edu.cn) and Yizhuo Zhang (zhangyzhorg.cn), Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, P. R. China.

Citation:
Song M, Yang J, Di M, Hong Y, Pan Q, Du Y, Xiang T, Liu J, Tang Y, Wang Q, Li Y, He J, Chen H, Zhao J, Weng D, Zhang Y, Xia JC. Alarmin IL-33 orchestrates antitumoral T cell responses to enhance sensitivity to 5-fluorouracil in colorectal cancer. Theranostics 2023; 13(5):1649-1668. doi:10.7150/thno.80483. https://www.thno.org/v13p1649.htm
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Abstract

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Rationale: Resistance to 5-fluorouracil (5-FU) chemotherapy remains the main barrier to effective clinical outcomes for patients with colorectal cancer (CRC). A better understanding of the detailed mechanisms underlying 5-FU resistance is needed to increase survival. Interleukin (IL)-33 is a newly discovered alarmin-like molecule that exerts pro- and anti-tumorigenic effects in various cancers. However, the precise role of IL-33 in CRC progression, as well as in the development of 5-FU resistance, remains unclear.

Methods: High-quality RNA-sequencing analyses were performed on matched samples from patients with 5-FU-sensitive and 5-FU-resistant CRC. The clinical and biological significance of IL-33, including its effects on both T cells and tumor cells, as well as its relationship with 5-FU chemotherapeutic activity were examined in ex vivo, in vitro and in vivo models of CRC. The molecular mechanisms underlying these processes were explored.

Results: IL-33 expressed by tumor cells was a dominant mediator of antitumoral immunity in 5-FU-sensitive patients with CRC. By binding to its ST2 receptor, IL-33 triggered CD4+ (Th1 and Th2) and CD8+ T cell responses by activating annexin A1 downstream signaling cascades. Mechanistically, IL-33 enhanced the sensitivity of CRC cells to 5-FU only in the presence of T cells, which led to the activation of both tumor cell-intrinsic apoptotic and immune killing-related signals, thereby synergizing with 5-FU to induce apoptosis of CRC cells. Moreover, injured CRC cells released more IL-33 and the T cell chemokines CXCL10 and CXCL13, forming a positive feedback loop to further augment T cell responses.

Conclusions: Our results identified a previously unrecognized connection between IL-33 and enhanced sensitivity to 5-FU. IL-33 created an immune-active tumor microenvironment by orchestrating antitumoral T cell responses. Thus, IL-33 is a potential predictive biomarker for 5-FU chemosensitivity and favorable prognosis and has potential as a promising adjuvant immunotherapy to improve the clinical benefits of 5-FU-based therapies in the treatment of CRC.

Keywords: IL-33, annexin A1, T cell response, 5-FU chemoresistance, adjuvant immunotherapy

Citation styles

APA
Song, M., Yang, J., Di, M., Hong, Y., Pan, Q., Du, Y., Xiang, T., Liu, J., Tang, Y., Wang, Q., Li, Y., He, J., Chen, H., Zhao, J., Weng, D., Zhang, Y., Xia, J.C. (2023). Alarmin IL-33 orchestrates antitumoral T cell responses to enhance sensitivity to 5-fluorouracil in colorectal cancer. Theranostics, 13(5), 1649-1668. https://doi.org/10.7150/thno.80483.

ACS
Song, M.; Yang, J.; Di, M.; Hong, Y.; Pan, Q.; Du, Y.; Xiang, T.; Liu, J.; Tang, Y.; Wang, Q.; Li, Y.; He, J.; Chen, H.; Zhao, J.; Weng, D.; Zhang, Y.; Xia, J.C. Alarmin IL-33 orchestrates antitumoral T cell responses to enhance sensitivity to 5-fluorouracil in colorectal cancer. Theranostics 2023, 13 (5), 1649-1668. DOI: 10.7150/thno.80483.

NLM
Song M, Yang J, Di M, Hong Y, Pan Q, Du Y, Xiang T, Liu J, Tang Y, Wang Q, Li Y, He J, Chen H, Zhao J, Weng D, Zhang Y, Xia JC. Alarmin IL-33 orchestrates antitumoral T cell responses to enhance sensitivity to 5-fluorouracil in colorectal cancer. Theranostics 2023; 13(5):1649-1668. doi:10.7150/thno.80483. https://www.thno.org/v13p1649.htm

CSE
Song M, Yang J, Di M, Hong Y, Pan Q, Du Y, Xiang T, Liu J, Tang Y, Wang Q, Li Y, He J, Chen H, Zhao J, Weng D, Zhang Y, Xia JC. 2023. Alarmin IL-33 orchestrates antitumoral T cell responses to enhance sensitivity to 5-fluorouracil in colorectal cancer. Theranostics. 13(5):1649-1668.

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