BACKGROUND Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma. RESULTS In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4 T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine's versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6 J E0771 murine breast cancer model. CONCLUSIONS Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies.

中文翻译：

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DNA甲基转移酶抑制剂guadecitabine靶向肿瘤诱导的骨髓生成，并与乳腺癌小鼠模型中的过继免疫疗法相结合，可恢复T细胞活性以减缓肿瘤生长。

背景技术髓样来源的抑制细胞（MDSCs）为癌症免疫治疗提出了重要的障碍，因为它们抑制了抗肿瘤细胞毒性T细胞应答。包括我们自己在内的以前的小组已经报告了某些化疗药物的骨髓衰竭作用。以前我们已经证明地西他滨增加了I类肿瘤细胞和肿瘤抗原的表达，增加了肿瘤细胞刺激T淋巴细胞的能力，体内耗尽了肿瘤诱导的MDSC，并增强了鼠类乳腺癌的免疫疗法。结果在这项研究中，我们通过测试下一代DNA甲基转移酶抑制剂（DNMTi）瓜地他滨来扩大该观察结果，该药物具有增强的血液循环稳定性。在BALB / cJ雌性小鼠中，使用4 T1鼠类乳腺癌模型，我们发现，瓜地他滨可通过防止过度的髓样细胞增殖和MDSC的全身蓄积，以T细胞依赖性方式显着降低肿瘤负担。其余的MDSC转变为抗原呈递表型。在我们以前的出版物的基础上，我们显示了瓜地他滨提高了过继转移的抗原经历的淋巴细胞的治疗效果，从而减少了肿瘤的生长并提高了总体生存率。我们还显示了瓜地他滨的多功能性，在C57BL / 6 J E0771鼠类乳腺癌模型中具有相似的肿瘤减少和免疫疗法增强作用。结论瓜地西他滨可以减少和改变MDSC，在体内抑制两种不同的鼠类乳腺癌的生长，并增强免疫治疗的效果。根据这些发现，