Department of Medical Research, Hsinchu MacKay Memorial Hospital, Hsinchu City, 30071, Taiwan.
Department of Dermatology, MacKay Memorial Hospital, Taipei City, 10449, Taiwan.
J Exp Clin Cancer Res. 2023 Jan 23;42(1):29. doi: 10.1186/s13046-023-02601-8.
The applicability and therapeutic efficacy of specific personalized immunotherapy for cancer patients is limited by the genetic diversity of the host or the tumor. Side-effects such as immune-related adverse events (IRAEs) derived from the administration of immunotherapy have also been observed. Therefore, regulatory immunotherapy is required for cancer patients and should be developed.
The cationic lipo-PEG-PEI complex (LPPC) can stably and irreplaceably adsorb various proteins on its surface without covalent linkage, and the bound proteins maintain their original functions. In this study, LPPC was developed as an immunoregulatory platform for personalized immunotherapy for tumors to address the barriers related to the heterogenetic characteristics of MHC molecules or tumor associated antigens (TAAs) in the patient population. Here, the immune-suppressive and highly metastatic melanoma, B16F10 cells were used to examine the effects of this platform. Adsorption of anti-CD3 antibodies, HLA-A2/peptide, or dendritic cells' membrane proteins (MP) could flexibly provide pan-T-cell responses, specific Th1 responses, or specific Th1 and Th2 responses, depending on the host needs. Furthermore, with regulatory antibodies, the immuno-LPPC complex properly mediated immune responses by adsorbing positive or negative antibodies, such as anti-CD28 or anti-CTLA4 antibodies.
The results clearly showed that treatment with LPPC/MP/CD28 complexes activated specific Th1 and Th2 responses, including cytokine release, CTL and prevented T-cell apoptosis. Moreover, LPPC/MP/CD28 complexes could eliminate metastatic B16F10 melanoma cells in the lung more efficiently than LPPC/MP. Interestingly, the melanoma resistance of mice treated with LPPC/MP/CD28 complexes would be reversed to susceptible after administration with LPPC/MP/CTLA4 complexes. NGS data revealed that LPPC/MP/CD28 complexes could enhance the gene expression of cytokine and chemokine pathways to strengthen immune activation than LPPC/MP, and that LPPC/MP/CTLA4 could abolish the LPPC/MP complex-mediated gene expression back to un-treatment.
Overall, we proved a convenient and flexible immunotherapy platform for developing personalized cancer therapy.
针对癌症患者的特定个性化免疫疗法的适用性和治疗效果受到宿主或肿瘤的遗传多样性的限制。此外，还观察到免疫疗法给药引起的免疫相关不良反应（IRAEs）。因此，需要对癌症患者进行调节性免疫治疗，并应开发这种治疗方法。
阳离子脂质体-聚乙二醇-聚亚乙基亚胺复合物（LPPC）可以稳定且不可替代地吸附其表面上的各种蛋白质，而结合的蛋白质保持其原始功能。在这项研究中，将 LPPC 开发为用于肿瘤的个性化免疫治疗的免疫调节平台，以解决与患者群体中 MHC 分子或肿瘤相关抗原（TAA）的异质性特征相关的障碍。在这里，使用免疫抑制性和高转移性黑色素瘤 B16F10 细胞来检查该平台的效果。根据宿主的需求，吸附抗 CD3 抗体、HLA-A2/肽或树突状细胞膜蛋白（MP）可以灵活地提供泛 T 细胞反应、特异性 Th1 反应或特异性 Th1 和 Th2 反应。此外，通过吸附阳性或阴性抗体，例如抗 CD28 或抗 CTLA4 抗体，免疫-LPPC 复合物可以适当调节免疫反应。
结果清楚地表明，用 LPPC/MP/CD28 复合物治疗可激活特异性 Th1 和 Th2 反应，包括细胞因子释放、CTL 和防止 T 细胞凋亡。此外，与 LPPC/MP 相比，LPPC/MP/CD28 复合物可以更有效地消除肺部的转移性 B16F10 黑色素瘤细胞。有趣的是，用 LPPC/MP/CD28 复合物治疗的小鼠的黑色素瘤耐药性在给予 LPPC/MP/CTLA4 复合物后会恢复为易感。NGS 数据显示，与 LPPC/MP 相比，LPPC/MP/CD28 复合物可以增强细胞因子和趋化因子途径的基因表达以增强免疫激活，而 LPPC/MP/CTLA4 可以将 LPPC/MP 复合物介导的基因表达消除回未治疗状态。
总的来说，我们为开发个性化癌症治疗方法证明了一种方便灵活的免疫治疗平台。
