Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea.
Division of Systems Biology and Bioengineering, Cell Factory Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Kwahak-ro, Daejeon, South Korea.
BMC Cancer. 2022 Jul 4;22(1):727. doi: 10.1186/s12885-022-09815-7.
The PD-L1 antibody is an immune checkpoint inhibitor (ICI) attracting attention. The third-generation anticancer drug has been proven to be very effective due to fewer side effects and higher tumor-specific reactions than conventional anticancer drugs. However, as tumors produce additional resistance in the host immune system, the effectiveness of ICI is gradually weakening. Therefore, it is very important to develop a combination therapy that increases the anticancer effect of ICI by removing anticancer resistance factors present around the tumor.
The syngeneic model was used (n = 6) to investigate the enhanced anti-tumor effect of PD-L1 antibody with the addition of PLAG. MB49 murine urothelial cancer cells were implanted into the C57BL/6 mice subcutaneously. PLAG at different dosages (50/100 mpk) was daily administered orally for another 4 weeks with or without 5 mpk PD-L1 antibody (10F.9G2). PD-L1 antibody was delivered via IP injection once a week.
The aPD-L1 monotherapy group inhibited tumor growth of 56% compared to the positive group, while the PLAG and aPD-L1 co-treatment inhibited by 89%. PLAG treatment effectively reduced neutrophils infiltrating localized in tumor and converted to a tumor microenvironment with anti-tumor effective T-cells. PLAG increased tumor infiltration of CD8 positive cytotoxic T-cell populations while effectively inhibiting the infiltration of neoplastic T-cells such as CD4/FoxP3. Eventually, neutrophil-induced tumor ICI resistance was resolved by restoring the neutrophil-to-lymphocyte ratio to the normal range. In addition, regulation of cytokine and chemokine factors that inhibit neutrophil infiltration and increase the killing activity of cytotoxic T cells was observed in the tumors of mice treated with PLAG + aPD-L1.
PLAG effectively turned the tumor-promoting microenvironment into a tumor-suppressing microenvironment. As a molecule that increases the anti-tumor effectiveness of aPD-L1, PLAG has the potential to be an essential and effective ICI co-therapeutic agent.
PD-L1 抗体是一种免疫检查点抑制剂（ICI），受到关注。与传统抗癌药物相比，第三代抗癌药物由于副作用较少，肿瘤特异性反应更高，已被证明非常有效。然而，由于肿瘤在宿主免疫系统中产生了额外的耐药性，ICI 的有效性逐渐减弱。因此，开发一种联合治疗方法非常重要，该方法通过去除肿瘤周围存在的抗癌耐药因素来提高 ICI 的抗癌效果。
使用同基因模型（n = 6）来研究 PD-L1 抗体与 PLAG 联合使用的增强抗肿瘤效果。MB49 鼠尿路上皮癌细胞皮下植入 C57BL/6 小鼠。每天口服给予不同剂量（50/100 mpk）的 PLAG，共 4 周，同时或不给予 5 mpk PD-L1 抗体（10F.9G2）。PD-L1 抗体通过 IP 注射每周一次给药。
与阳性组相比，aPD-L1 单药治疗组抑制肿瘤生长 56%，而 PLAG 和 aPD-L1 联合治疗组抑制 89%。PLAG 治疗有效减少了局部浸润肿瘤的中性粒细胞，并将肿瘤微环境转化为具有抗肿瘤有效 T 细胞的环境。PLAG 增加了肿瘤浸润的 CD8 阳性细胞毒性 T 细胞群体，同时有效抑制了肿瘤 T 细胞（如 CD4/FoxP3）的浸润。最终，通过将中性粒细胞诱导的肿瘤 ICI 耐药性恢复到正常范围，解决了中性粒细胞诱导的肿瘤 ICI 耐药性。此外，在接受 PLAG+aPD-L1 治疗的小鼠肿瘤中观察到抑制中性粒细胞浸润和增加细胞毒性 T 细胞杀伤活性的细胞因子和趋化因子因子的调节。
PLAG 有效地将促进肿瘤的微环境转化为抑制肿瘤的微环境。作为一种增加 aPD-L1 抗肿瘤效果的分子，PLAG 有可能成为一种必不可少且有效的 ICI 联合治疗药物。
