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

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 cellintrinsic 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-FUbased therapies in the treatment of CRC.