PO.IM01.03 · 免疫学
靶向蛋白降解疫苗（PROTAX）用于稳健的肿瘤联合免疫治疗
Proteolysis-targeting vaccines, or PROTAX, for robust tumor combination immunotherapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目前的多肽疫苗诱导的抗肿瘤T细胞反应有限，导致肿瘤治疗疗效欠佳。在此，我们提出了靶向蛋白降解疫苗（proteolysis-targeting vaccines，PROTAX），其可促进抗原的蛋白水解加工和交叉呈递，从而增强T细胞反应，实现与免疫检查点阻断（ICB）联合的稳健肿瘤免疫治疗。PROTAX是通过连接子将多肽抗原与E3连接酶结合配体偶联而成的。在抗原呈递细胞（APC）中，PROTAX与E3连接酶结合，迅速使PROTAX抗原泛素化，促进抗原经蛋白酶体进行蛋白水解加工，从而促进抗原向T细胞的交叉呈递。在小鼠中，PROTAX既提升了针对抗原的CD8⁺ T细胞反应的数量，也提升了其质量，这些抗原包括多价黑色素瘤相关抗原Trp2-gp100-Trp1（TgT）和合成长肽人乳头瘤病毒（HPV）-16 E7。在荷黑色素瘤小鼠中，PROTAX-TgT + ICB重塑了肿瘤免疫微环境并提高了肿瘤完全消退（CR）率，且这一作用依赖于经典1型树突状细胞（cDC1）和CD8⁺ T细胞。PROTAX-TgT + ICB根除了100%的大体积Braf V600E SM1黑色素瘤（约300 mm³），并提高了M3黑色素瘤以及TgT抗原表达低、高度免疫抑制的Braf CA + M2黑色素瘤的CR率。在Braf V600E/Pten-/-小鼠的自发性Braf V600E黑色素瘤中，PROTAX-TgT + ICB减轻了肿瘤内分子和细胞层面的免疫抑制，抑制了肿瘤进展和转移，并将小鼠中位生存期从初始肿瘤治疗后21天延长至66天。类似地，PROTAX-E7 + ICB使大体积TC-1肿瘤（约300 mm³）达到43%的CR。在来自健康供者和HPV-16⁺头颈部鳞状细胞癌（HNSCC）患者的人白细胞抗原（HLA）-A02:01人PBMC中，HLA-A02:01限制性的三价PROTAX E6-(E7)2促进了三特异性CD8⁺ T细胞反应，其特征为抗原特异性T细胞扩增增强以及人干扰素-γ（IFN-gamma）和肿瘤坏死因子-α（TNF-alpha）的产生增加。因此，PROTAX具有实现稳健肿瘤联合免疫治疗的潜力。
查看英文原文 English abstract
Current peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal tumor therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAX) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust tumor immunotherapy in combination with immune checkpoint blockade (ICB). PROTAX are peptide antigens conjugated with a E3 ligase-binding ligand via linkers. In antigen-presenting cells (APCs), PROTAX bind to E3 ligases to rapidly ubiquitinate PROTAX antigens, facilitating antigen proteolytic processing by proteasome, and thereby promoting antigen cross-presentation to T cells. In mice, PROTAX promoted both the quantity and quality of CD8⁺ T cell responses against antigens, such as multivalent melanoma-associated antigen Trp2-gp100-Trp1 (TgT) and synthetic long peptide human papillomavirus (HPV)-16 E7. In melanoma-bearing mice, PROTAX-TgT + ICB remodeled the tumor immune microenvironment and enhanced tumor complete regression (CR) rates, in a manner dependent on classic type-1 dendritic cells (cDC1) and CD8 + T cells. PROTAX-TgT + ICB eradicated 100% large Braf V600E SM1 melanomas (~300 mm³), and promoted the CR rates of M3 melanoma and highly immunosuppressive Braf CA + M2 melanoma with low TgT antigen expression. In an autochthonous Braf V600E melanoma in Braf V600E/Pten-/- mice, PROTAX-TgT + ICB reduced the molecular and cellular immunosuppression in the tumor, inhibited tumor progression and metastasis, and extended mouse median survival from 21 days to 66 days post initial tumor treatment. Similarly, PROTAX-E7 + ICB resulted in 43% CR of large TC-1 tumors (~300 mm³). In human leukocyte antigen (HLA)-A02:01 human PBMCs from healthy donors and HPV-16 + Head and Neck Squamous Cell Carcinoma (HNSCC) patients, HLA-A02:01-restricted trivalent PROTAX E6-(E7)2 promoted tri-specific CD8 + T cell responses, characterized with enhanced antigen-specific T cell expansion and production of human interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Therefore, PROTAX hold the potential for robust tumor combination immunotherapy.
利益披露 Disclosure
W. li, None..
S. Wang, None..
G. J. Zhu, None.