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Abstract：
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.
摘要：
原理：对5-氟尿嘧啶（5-FU）化疗的耐药性仍然是结直肠癌（CRC）患者有效临床结局的主要障碍。需要更好地理解5-FU抗性的详细机制以增加存活率。白细胞介素（IL）-33是一种新发现的alarmin样分子，在各种癌症中发挥促和抗肿瘤作用。然而,IL-33在CRC进展中的确切作用，以及在5-FU抗性的发展中，尚不清楚。方法：对来自5-FU敏感和5-FU耐药CRC患者的匹配样本进行高质量RNA测序分析。IL-33的临床和生物学意义，包括其对T细胞和肿瘤细胞的影响，以及它与5-FU化疗活性的关系在离体检查，CRC的体外和体内模型。探索了这些过程的分子机制。结果：在5-FU敏感的CRC患者中，肿瘤细胞表达的IL-33是抗肿瘤免疫的主要介质。通过结合它的ST2受体，IL-33通过激活膜联蛋白A1下游信号传导级联来触发CD4+(Th1和Th2)和CD8+T细胞应答。机械上,IL-33仅在T细胞存在下增强CRC细胞对5-FU的敏感性,这导致肿瘤细胞固有的凋亡和免疫杀伤相关信号的激活，从而与5-FU协同诱导CRC细胞凋亡。此外，损伤的CRC细胞释放更多的IL-33和T细胞趋化因子CXCL10和CXCL13，形成正反馈回路以进一步增强T细胞应答。结论：我们的结果确定了IL-33与对5-FU的敏感性增强之间的先前未识别的联系。IL-33通过协调抗肿瘤T细胞反应创造了免疫活性肿瘤微环境。因此，IL-33是5-FU化学敏感性和良好预后的潜在预测生物标志物，并且具有作为有希望的辅助免疫疗法的潜力，以改善基于5-FU的疗法在CRC治疗中的临床益处。
