Vascular Normalization Was Associated with Colorectal Tumor Regression upon Anti-PD-L1 Combinational Therapy.
Vascular Normalization Was Associated with Colorectal Tumor Regression upon Anti-PD-L1 Combinational Therapy.
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DOI：
10.1155/2023/5867047
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发表时间：
2023
影响因子：
4.1
通讯作者：
Huang, Yuhui
中科院分区：
文献类型：
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作者：
Zhang, Yan;Gao, Jiayan;He, Yan;Qi, Ziwei;Qian, Long;Chen, Wanpei;Xu, Haiyan;Yue, Yanhua;Mao, Xunyuan;Guo, Shuxin;Zhou, Yan;Zhou, Shuru;Qin, Songbing;Zhang, Xueguang;Huang, Yuhui
抗PD-L1治疗具有持久的疗效，但仅在一小部分癌症患者中有效。免疫抑制性肿瘤微环境（TME）是阻碍癌症免疫治疗的关键障碍。在这里，我们发现，抗PD-L1治疗加上CD 4 + T细胞耗竭诱导结直肠肿瘤消退和血管正常化，而单药治疗仅延缓肿瘤生长而不影响肿瘤血管。此外，PD-L1阻断和CD 4 + T细胞耗竭同时消除了肿瘤内PD-L1+淋巴和骨髓细胞群，同时增加了CD 44 + CD 69 + CD 8+、中枢记忆CD 44 + CD 62 L + CD 8+和效应记忆CD 44 + CD 62 L − CD 8 + T细胞的比例，表明TME中免疫抑制细胞群减少和CD 8 + T细胞活化。此外，抗PD-L1治疗降低了肿瘤内PD-L1+免疫细胞的比例，并以CD 8 + T细胞依赖性方式抑制肿瘤生长。总之，这些结果表明，抗PD-L1治疗通过CD 8 + T细胞诱导肿瘤血管正常化和结直肠肿瘤消退，这被CD 4 + T细胞拮抗。我们的研究结果揭示了抗PD-L1治疗后结直肠肿瘤模型中肿瘤消退和血管正常化的正相关性，为提高其疗效提供了潜在的新策略。
Anti-PD-L1 therapy exhibits durable efficacy, but only in a small fraction of cancer patients. The immunosuppressive tumor microenvironment (TME) is a crucial obstacle that impedes cancer immunotherapy. Here, we found that anti-PD-L1 therapy coupled with CD4+ T cell depletion induced colorectal tumor regression and vascular normalization, while monotherapy only retarded tumor growth without affecting the tumor vasculature. Moreover, simultaneous PD-L1 blockade and CD4+ T cell depletion eradicated intratumoral PD-L1+ lymphoid and myeloid cell populations, while additively elevating the proportions of CD44+CD69+CD8+, central memory CD44+CD62L+CD8+, and effector memory CD44+CD62L−CD8+ T cells, suggesting a reduction in immunosuppressive cell populations and the activation of CD8+ T cells in the TME. Moreover, anti-PD-L1 therapy reduced the proportions of intratumoral PD-L1+ immune cells and suppressed tumor growth in a CD8+ T cell dependent manner. Together, these results suggest that anti-PD-L1 therapy induces tumor vascular normalization and colorectal tumor regression via CD8+ T cells, which is antagonized by CD4+ T cells. Our findings unveil the positive correlation of tumor regression and vascular normalization in colorectal tumor models upon anti-PD-L1 therapy, providing a potential new strategy to improve its efficacy.