Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
Bristol-Myers Squibb Research and Development, Princeton, New Jersey.
Cancer Immunol Res. 2017 Feb;5(2):157-169. doi: 10.1158/2326-6066.CIR-16-0061-T. Epub 2017 Jan 10.
Dasatinib, a broad-range tyrosine kinase inhibitor, induces rapid mobilization of lymphocytes and clonal expansion of cytotoxic cells in leukemia patients. Here, we investigated whether dasatinib could induce beneficial immunomodulatory effects in solid tumor models. The effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma). Both peripheral blood (PB) and tumor samples were immunophenotyped during treatment. Although in vitro dasatinib displayed no direct cytotoxicity to B16 melanoma cells, a significant decrease in tumor growth was observed in dasatinib-treated mice compared with vehicle-treated group. Further, dasatinib-treated melanoma-bearing mice had an increased proportion of CD8 T cells in PB, together with a higher amount of tumor-infiltrating CD8 T cells. Dasatinib-mediated antitumor efficacy was abolished when CD4 and CD8 T cells were depleted with antibodies. Results were confirmed in sarcoma, colon, and breast cancer models, and in all cases mice treated daily with dasatinib had a significant decrease in tumor growth. Detailed immunophenotyping of tumor tissues with CyTOF indicated that dasatinib had reduced the number of intratumoral regulatory T cells in all tumor types. To conclude, dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation. The assessment of synergistic combinatorial therapies with other immunomodulatory drugs or targeted small-molecule oncokinase inhibitors is warranted in future clinical trials. Cancer Immunol Res; 5(2); 157-69. ©2017 AACR.
达沙替尼是一种广谱酪氨酸激酶抑制剂，可诱导白血病患者淋巴细胞快速动员和细胞毒性细胞克隆扩增。在此，我们研究了达沙替尼是否可在实体瘤模型中诱导有益的免疫调节作用。在四个不同的同基因小鼠模型（B16.OVA 黑色素瘤、1956 肉瘤、MC38 结肠和 4T1 乳腺癌）中研究了其对肿瘤生长和免疫系统的影响。在治疗过程中对外周血（PB）和肿瘤样本进行免疫表型分析。尽管达沙替尼在体外对 B16 黑色素瘤细胞没有直接的细胞毒性，但与对照组相比，达沙替尼治疗组的肿瘤生长明显减少。此外，达沙替尼治疗的荷瘤小鼠 PB 中 CD8 T 细胞的比例增加，同时肿瘤浸润的 CD8 T 细胞数量也增加。用抗体耗尽 CD4 和 CD8 T 细胞可消除达沙替尼的抗肿瘤功效。在肉瘤、结肠和乳腺癌模型中得到了证实，并且在所有情况下，每天用达沙替尼治疗的小鼠肿瘤生长均显著减少。CyTOF 对肿瘤组织的详细免疫表型分析表明，达沙替尼减少了所有肿瘤类型中的肿瘤内调节性 T 细胞数量。总之，达沙替尼能够减缓各种实体瘤模型的肿瘤生长，这与血液/肿瘤 T 细胞免疫调节有关。在未来的临床试验中，有必要评估与其他免疫调节药物或靶向小分子癌激酶抑制剂的协同联合疗法。Cancer Immunol Res; 5(2); 157-69. ©2017 AACR.
