Translational nanomedicine potentiates immunotherapy in sarcoma by normalizing the microenvironment
Translational nanomedicine potentiates immunotherapy in sarcoma by normalizing the microenvironment
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DOI：
10.1016/j.jconrel.2022.12.016
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发表时间：
2022-12-21
影响因子：
10.8
通讯作者：
Stylianopoulos, Triantafyllos
中科院分区：
文献类型：
--
作者：
Mpekris, Fotios;Panagi, Myrofora;Stylianopoulos, Triantafyllos
基于纳米载体的化学免疫疗法在临床试验中取得了成功，了解其对肿瘤微环境的影响可以促进进一步提高这些方案疗效的策略的发展。NC-6300（表柔比星胶束）在肉瘤患者中显示出抗肿瘤活性，但是否与免疫检查点抑制联合使用尚不清楚。在此，我们在骨肉瘤和纤维肉瘤小鼠模型中测试了NC-6300联合抗pd - l1抗体。我们发现，肉瘤对NC-6300的反应呈剂量依赖性，而抗pd - l1的疗效即使在NC-6300的剂量低于最大耐受剂量的10%时也会增强。此外，NC-6300在增加抗pd - l1抗体诱导的肿瘤生长延迟方面比最大耐受剂量的多柔比星更有效。我们研究了这种组合的作用机制。NC-6300诱导免疫原性细胞死亡，其对抗pd - l1抗体疗效的影响依赖于T细胞。此外，NC-6300通过增加血管成熟度和减少纤维化，使肿瘤微环境正常化（即，改善病理生理向正常表型转变）。因此，与抗pd - l1抗体联合使用可增加肿瘤内T细胞的密度和增殖。综上所述，NC-6300增强了肉瘤的免疫检查点抑制，在开发基于纳米载体的化学免疫治疗方案时，应研究肿瘤微环境的正常化。
Nanocarrier-based chemo-immunotherapy has succeeded in clinical trials and understanding its effect on the tumor microenvironment could facilitate development of strategies to increase efficacy of these regimens further. NC-6300 (epirubicin micelle) demonstrates anti-tumor activity in sarcoma patients, but whether it is combinable with immune checkpoint inhibition is unclear. Here, we tested NC-6300 combined with anti-PD-L1 antibody in mouse models of osteosarcoma and fibrosarcoma. We found that sarcoma responds to NC-6300 in a dose-dependent manner, while anti-PD-L1 efficacy is potentiated even at a dose of NC-6300 less than 10% of the maximum tolerated dose. Furthermore, NC-6300 is more effective than the maximum tolerated dose of doxo-rubicin in increasing the tumor growth delay induced by anti-PD-L1 antibody. We investigated the mechanism of action of this combination. NC-6300 induces immunogenic cell death and its effect on the efficacy of anti-PD-L1 antibody is dependent on T cells. Also, NC-6300 normalized the tumor microenvironment (i.e., ameliorated pathophysiology towards normal phenotype) as evidenced through increased blood vessel maturity and reduced fibrosis. As a result, the combination with anti-PD-L1 antibody increased the intratumor density and proliferation of T cells. In conclusion, NC-6300 potentiates immune checkpoint inhibition in sarcoma, and normalization of the tumor microenvironment should be investigated when developing nanocarrier-based chemo-immunotherapy regimens.