Department of Immune Medicine, National Cancer Center Research Institute, National Cancer Center.
Division of Respiratory Medicine, Kyorin University School of Medicine.
Biol Pharm Bull. 2022;45(1):34-41. doi: 10.1248/bpb.b21-00493.
Imatinib mesylate is a potent tyrosine kinase inhibitor that may induce immunological effects, such as inhibition of immune suppressive cells; but, how it modulates the immune system remains to be completely elucidated. In this study, we showed that cell proliferation of CT26 colon cancer and Lewis lung carcinoma (3LL) lung cancer cells was not inhibited by imatinib in vitro, although its administration significantly suppressed the growth of CT26, but not 3LL, subcutaneous tumors, and prolonged survival in CT26 tumor-bearing mice. Further, we examined the expression of immune cell-related molecules in the tumors to elucidate the differences in imatinib-mediated antitumor effects between CT26 and 3LL tumors. The nCounter assay showed that the expression of CD8 and CD8 T cell-recruiting chemokine genes was significantly elevated in imatinib-treated CT26 tumors than that in control tumors; however, the gene expression remained unchanged in imatinib-treated or control 3LL tumors. Furthermore, frequency of interferon-γ (IFN-γ) CD8 T cells was increased in imatinib-treated CT26 tumors than control tumors, indicating induction of antitumor immunity by imatinib. The analysis indicates that imatinib promotes infiltration of effector T cells in tumors by upregulating expression of cytokines that recruit CD8 T cells in the tumor microenvironment, which may lead to a strong antitumor effect.
甲磺酸伊马替尼是一种有效的酪氨酸激酶抑制剂，可能会诱导免疫效应，如抑制免疫抑制细胞；但是，它如何调节免疫系统仍有待完全阐明。在这项研究中，我们表明，伊马替尼在体外不会抑制 CT26 结肠癌细胞和 Lewis 肺癌（3LL）肺癌细胞的增殖，尽管其给药显著抑制了 CT26 的生长，但不抑制 3LL 的生长，并延长了 CT26 荷瘤小鼠的存活时间。此外，我们检测了肿瘤中免疫细胞相关分子的表达，以阐明伊马替尼介导的 CT26 和 3LL 肿瘤抗肿瘤作用的差异。nCounter 分析显示，与对照组肿瘤相比，伊马替尼处理的 CT26 肿瘤中 CD8 和 CD8 T 细胞募集趋化因子基因的表达显著升高；然而，伊马替尼处理或对照组 3LL 肿瘤中的基因表达保持不变。此外，与对照组肿瘤相比，伊马替尼处理的 CT26 肿瘤中干扰素-γ（IFN-γ）CD8 T 细胞的频率增加，表明伊马替尼诱导了抗肿瘤免疫。分析表明，伊马替尼通过上调肿瘤微环境中募集 CD8 T 细胞的细胞因子的表达，促进效应 T 细胞在肿瘤中的浸润，从而可能产生强烈的抗肿瘤作用。
