Mantilla-Rojas Carolina, Velasquez Fred C, Morton Janelle E, Clemente Leticia C, Parra Edwin R, Torres-Cabala Carlos, Sevick-Muraca Eva M
Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA.
Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Cancers (Basel). 2022 Apr 4;14(7):1823. doi: 10.3390/cancers14071823.
An infusion of checkpoint blockade immunotherapy (CBI) has revolutionized cancer treatments for some patients, but the majority of patients experience disappointing responses. Because adaptive immune responses are mounted by the concentrated assembly of antigens, immune cells, and mediators in the secluded and protective environment of draining lymph nodes (dLNs), we hypothesize that lymphatic delivery of CBI (αCTLA-4 and αPD-1) to tumor dLNs (tdLNs) improves anti-tumor responses over intravenous (i.v.) administration, and that vaccination against tumor associated antigen (TAA) further enhances these responses. Mono- and combination CBI were administered i.v. or through image-guided intradermal (i.d.) injection to reach tdLNs in vaccinated and unvaccinated animals bearing either primary or orthotopically metastasizing B16F10 melanoma. Vaccination and boost against TAA, Melan-A, was accomplished with virus-like particles (VLP) directed to tdLNs followed by VLP boost after CBI administration. Lymphatic delivery of CBIs reduced primary tumor size and metastatic tumor burden, alleviated the pro-tumorigenic immune environment, and improved survival over systemic administration of CBIs. Animals receiving CBIs lymphatically exhibited significantly enhanced survival over those receiving therapies administered partially or completely through systemic routes. By combining vaccination and CBI for effective T-cell priming in the protected environment of dLNs, anti-tumor responses may be improved.
检查点阻断免疫疗法（CBI）的输注彻底改变了一些患者的癌症治疗方式，但大多数患者的反应令人失望。由于适应性免疫反应是在引流淋巴结（dLNs）这个隐蔽且具有保护作用的环境中，通过抗原、免疫细胞和介质的集中组装而产生的，我们推测将CBI（αCTLA - 4和αPD - 1）经淋巴管递送至肿瘤引流淋巴结（tdLNs）比静脉内（i.v.）给药能改善抗肿瘤反应，并且针对肿瘤相关抗原（TAA）的疫苗接种能进一步增强这些反应。对患有原发性或原位转移性B16F10黑色素瘤的已接种和未接种疫苗的动物，通过静脉内或经图像引导的皮内（i.d.）注射给予单药和联合CBI，以到达tdLNs。针对TAA黑色素A的疫苗接种和加强免疫是通过靶向tdLNs的病毒样颗粒（VLP）完成的，随后在给予CBI后进行VLP加强免疫。与全身给予CBI相比，经淋巴管递送CBI可减小原发性肿瘤大小和转移性肿瘤负担，减轻促肿瘤免疫环境，并提高生存率。与通过全身途径部分或完全给予治疗的动物相比，经淋巴管接受CBI的动物生存率显著提高。通过在dLNs的受保护环境中联合疫苗接种和CBI以有效启动T细胞，可能会改善抗肿瘤反应。
