联合靶向 STAT3 的高吸收型姜黄素的 PD-1 阻断增强抗肿瘤作用。

Enhanced anti-tumor effects of the PD-1 blockade combined with a highly absorptive form of curcumin targeting STAT3.

机构信息

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Department of Immunology, School of Medicine, International University of Health and Welfare, Chiba, Japan.

出版信息

Cancer Sci. 2020 Dec;111(12):4326-4335. doi: 10.1111/cas.14675. Epub 2020 Oct 20.

Abstract

PD-1/PD-L1 immune checkpoint inhibitors are promising cancer immunotherapies however responses are still limited and the development of more effective combination immunotherapy is needed. We previously reported that STAT3 activation in cancer cells and immune cells was involved in immune-resistant mechanisms. In this study, we evaluated the effect of highly absorptive forms of curcumin extracts and synthetic curcumin on anti-tumor T cell responses. The curcumin po administration resulted in the significant augmentation of in vivo induction of tumor antigen-specific T cells through restoration of dendritic cells (DCs) by inhibiting directly STAT3 in DCs and indirectly via reduced IL-6 production from STAT3 activated cancer cells in 2 syngeneic MC38 and CT26 murine tumor models. Curcumin also showed direct DC enhancing activity and enhanced T cell induction for the immunized antigens in non-tumor-bearing mice and human hosts. Curcumin restored DC functions in xenogeneic nude mouse model implanted with high IL-6-producing human clear cell ovarian cancer cells. The combination of curcumin and PD-1/PD-L1 Abs demonstrated a synergistic anti-tumor activity in MC38 murine tumor models. These results indicated that curcumin augments the induction of tumor antigen-specific T cells by restoring the T cell stimulatory activity of DCs targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD-1/PD-L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers.

摘要

PD-1/PD-L1 免疫检查点抑制剂是很有前途的癌症免疫疗法,然而,反应仍然有限,需要开发更有效的联合免疫疗法。我们之前报道过,癌细胞和免疫细胞中的 STAT3 激活与免疫抵抗机制有关。在这项研究中,我们评估了高吸收率的姜黄素提取物和合成姜黄素对抗肿瘤 T 细胞反应的影响。姜黄素 po 给药通过抑制 DC 中的 STAT3 直接作用,以及通过减少 STAT3 激活的癌细胞中 IL-6 的产生间接作用,导致体内肿瘤抗原特异性 T 细胞的诱导显著增强,这两种方法在两种同源 MC38 和 CT26 小鼠肿瘤模型中均得到了证实。姜黄素还显示出直接的 DC 增强活性,并在非荷瘤小鼠和人宿主中增强了对免疫抗原的 T 细胞诱导。姜黄素在植入高 IL-6 产生的人透明细胞卵巢癌细胞的异种裸鼠模型中恢复了 DC 功能。姜黄素与 PD-1/PD-L1 Abs 的组合在 MC38 小鼠肿瘤模型中显示出协同的抗肿瘤活性。这些结果表明,姜黄素通过恢复癌细胞和免疫细胞中激活的 STAT3 的 DC 刺激 T 细胞活性,增强了肿瘤抗原特异性 T 细胞的诱导。姜黄素与 PD-1/PD-L1 Ab 的联合免疫疗法是开发针对各种癌症的有效免疫疗法的一种有吸引力的策略。

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