Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Chonnam National University Medical School, Gwangju, South Korea.
Commun Biol. 2023 Jan 12;6(1):31. doi: 10.1038/s42003-022-04403-8.
Primary and adaptive resistance to immune checkpoint therapies (ICT) represent a considerable obstacle to achieving enhanced overall survival. Innate immune activators have been actively pursued for their antitumor potential. Herein we report that a syngeneic 4T1 mammary carcinoma murine model for established highly-refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with either the TLR5 agonist flagellin or CBLB502, a flagellin derivative, in combination with antibodies targeting CTLA-4 and PD-1. Long-term survivor mice showed immunologic memory upon tumor re-challenge and a distinctive immune activating cytokine profile that engaged both innate and adaptive immunity. Low serum levels of G-CSF and CXCL5 (as well as high IL-15) were candidate predictive biomarkers correlating with enhanced survival. CBLB502-induced enhancement of ICT was also observed in poorly immunogenic B16-F10 melanoma tumors. Combination immune checkpoint therapy plus TLR5 agonists may offer a new therapeutic strategy to treat ICT-refractory solid tumors.
原发和适应性耐药性对免疫检查点治疗（ICT）构成了实现整体生存改善的重大障碍。先天免疫激活剂因其抗肿瘤潜力而受到积极研究。在此，我们报告称，一种用于已建立的高度难治性三阴性乳腺癌的同基因 4T1 乳腺肿瘤鼠模型，当用 TLR5 激动剂鞭毛蛋白或鞭毛蛋白衍生物 CBLB502 联合针对 CTLA-4 和 PD-1 的抗体进行肿瘤内治疗时，显示出生存时间延长。长期存活的小鼠在肿瘤再次挑战时表现出免疫记忆，并表现出独特的免疫激活细胞因子谱，涉及先天和适应性免疫。低血清水平的 G-CSF 和 CXCL5（以及高 IL-15）是与生存改善相关的候选预测性生物标志物。在免疫原性差的 B16-F10 黑色素瘤肿瘤中也观察到 CBLB502 诱导的 ICT 增强。联合免疫检查点治疗加 TLR5 激动剂可能为治疗 ICT 耐药性实体瘤提供新的治疗策略。
