Department of Medical and Molecular Genetics.
Department of Pediatrics.
JCI Insight. 2020 May 7;5(9):136073. doi: 10.1172/jci.insight.136073.
Immune checkpoint blockade immunotherapy delivers promising clinical results in colorectal cancer (CRC). However, only a fraction of cancer patients develop durable responses. The tumor microenvironment (TME) negatively impacts tumor immunity and subsequently clinical outcomes. Therefore, there is a need to identify other checkpoint targets associated with the TME. Early-onset factors secreted by stromal cells as well as tumor cells often help recruit immune cells to the TME, among which are alarmins such as IL-33. The only known receptor for IL-33 is stimulation 2 (ST2). Here we demonstrated that high ST2 expression is associated with poor survival and is correlated with low CD8+ T cell cytotoxicity in CRC patients. ST2 is particularly expressed in tumor-associated macrophages (TAMs). In preclinical models of CRC, we demonstrated that ST2-expressing TAMs (ST2+ TAMs) were recruited into the tumor via CXCR3 expression and exacerbated the immunosuppressive TME; and that combination of ST2 depletion using ST2-KO mice with anti-programmed death 1 treatment resulted in profound growth inhibition of CRC. Finally, using the IL-33trap fusion protein, we suppressed CRC tumor growth and decreased tumor-infiltrating ST2+ TAMs. Together, our findings suggest that ST2 could serve as a potential checkpoint target for CRC immunotherapy.
免疫检查点阻断免疫疗法在结直肠癌 (CRC) 中带来了有前景的临床结果。然而，只有一部分癌症患者产生持久的反应。肿瘤微环境 (TME) 对肿瘤免疫产生负面影响，进而影响临床结果。因此，有必要确定与 TME 相关的其他检查点靶标。基质细胞和肿瘤细胞早期分泌的因子通常有助于将免疫细胞募集到 TME 中，其中包括白细胞介素 33 (IL-33) 等警报素。IL-33 的唯一已知受体是刺激 2 (ST2)。在这里，我们证明高 ST2 表达与较差的生存相关，并且与 CRC 患者中 CD8+ T 细胞细胞毒性降低相关。ST2 在肿瘤相关巨噬细胞 (TAMs) 中特异性表达。在 CRC 的临床前模型中，我们证明了通过 CXCR3 表达募集到肿瘤中的 ST2 表达 TAMs (ST2+ TAMs) 加剧了免疫抑制性 TME；并且使用 ST2-KO 小鼠进行 ST2 耗竭与抗程序性死亡 1 治疗相结合，导致 CRC 显著抑制生长。最后，使用 IL-33 陷阱融合蛋白，我们抑制了 CRC 肿瘤生长并减少了肿瘤浸润的 ST2+ TAMs。总之，我们的研究结果表明，ST2 可作为 CRC 免疫治疗的潜在检查点靶标。
