The Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
The Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Oncoimmunology. 2023 May 27;12(1):2218782. doi: 10.1080/2162402X.2023.2218782. eCollection 2023.
Eribulin mesylate (ERB) is a synthetic analog of halichondrin B, inhibiting tumor cell growth by disrupting microtubule function. Recently, anticancer drugs have been shown to not only act directly on tumor cells but also to exert antitumor effects by modifying the tumor environment. Although ERB has also been speculated to modify the tumor microenvironment including the immune response to tumors, the precise mechanism remains unclear. In our study, ERB suppressed the tumor growth of MC38 colon cancer in wildtype mice, whereas ERB failed to inhibit the tumor growth in Rag1-deficient mice which lack both B and T cells. Moreover, depletion of either CD4 or CD8 T cells abrogated the antitumor effect of ERB, indicating that both CD4 and CD8 T cells play an important role in ERB-induced antitumor effects. Furthermore, ERB treatment increased the number of tumor infiltrating lymphocytes (TILs) as well as the expression of activation markers (CD38 and CD69), immune checkpoint molecules (LAG3, TIGIT and Tim3) and cytotoxic molecules (granzyme B and perforin) in TILs. ERB upregulated E-cadherin expression in MC38. CD103 is a ligand of E-cadherin and induces T-cell activation. ERB increased the proportion of CD103 cells in both CD4 and CD8 TILs. The ERB-induced antitumor effect with the increased TIL number and the increased expression of activation markers, inhibitory checkpoint molecules and cytotoxic molecules in TILs was abrogated in CD103-deficient mice. Collectively, these results suggest that ERB exerts antitumor effects by upregulation of E-cadherin expression in tumor cells and subsequent activation of CD103 TILs.
甲磺酸艾日布林（ERB）是一种卤虫酮 B 的合成类似物，通过破坏微管功能抑制肿瘤细胞生长。最近，抗癌药物不仅被证明可以直接作用于肿瘤细胞，还可以通过改变肿瘤环境发挥抗肿瘤作用。虽然 ERB 也被推测可以修饰肿瘤微环境，包括对肿瘤的免疫反应，但确切的机制仍不清楚。在我们的研究中，ERB 抑制了野生型小鼠 MC38 结肠癌细胞的肿瘤生长，而在缺乏 B 和 T 细胞的 Rag1 缺陷型小鼠中，ERB 未能抑制肿瘤生长。此外，耗尽 CD4 或 CD8 T 细胞均可消除 ERB 的抗肿瘤作用，表明 CD4 和 CD8 T 细胞在 ERB 诱导的抗肿瘤作用中都发挥了重要作用。此外，ERB 治疗增加了肿瘤浸润淋巴细胞（TIL）的数量，并增加了 TIL 中激活标记物（CD38 和 CD69）、免疫检查点分子（LAG3、TIGIT 和 Tim3）和细胞毒性分子（颗粒酶 B 和穿孔素）的表达。ERB 上调了 MC38 中的 E-钙黏蛋白表达。CD103 是 E-钙黏蛋白的配体，可诱导 T 细胞激活。ERB 增加了 CD4 和 CD8 TIL 中 CD103 细胞的比例。在 CD103 缺陷型小鼠中，ERB 诱导的抗肿瘤作用，以及 TIL 中 T 细胞激活标志物、抑制性检查点分子和细胞毒性分子表达的增加，均被消除。综上所述，这些结果表明，ERB 通过上调肿瘤细胞中的 E-钙黏蛋白表达，并随后激活 CD103 TIL，发挥抗肿瘤作用。
