免疫检查点阻断（ICB）疗法是晚期癌症患者的重要治疗方法；然而，只有一小部分患有某些类型癌症的患者获得持久缓解。癌症疫苗是一种增强患者免疫反应的有吸引力的策略，但人们对免疫是否以及如何诱导长期肿瘤免疫重编程和阻止癌症进展知之甚少。我们开发了一种临床相关的遗传癌症小鼠模型，其中肝细胞偶尔发生致癌转化。我们比较了早期散发性病变小鼠与晚期病变小鼠中肿瘤特异性 CD8 T 细胞 (TST) 的分化情况，并测试了免疫治疗策略（包括疫苗接种和 ICB）如何影响 TST 功能和肝癌进展。 SV40 大 T 抗原 (TAG) 会发生 TAG 癌基因的自发重组和激活，导致罕见的早期癌性 TAG 表达病变，并不可避免地发展为肝癌。我们通过流式细胞术评估了早期和晚期肝损伤小鼠中肿瘤/TAG特异性CD8 T细胞的免疫表型（CD44、PD1、TCF1和TOX表达）和功能（TNFα和IFNγ细胞因子产生）。我们单独或与 ICB 联合对小鼠进行疫苗接种，以测试这些免疫治疗干预措施是否可以阻止肝癌进展并提高生存率。在患有早期病变的小鼠中，TST 的一个子集是 PD1 TCF1 TOX-，并且可以产生 IFNγ，而 TST 存在于肝癌中。患有晚期肝癌的小鼠患有PD1 TCF1lo/- TOX并且无法产生效应细胞因子。引人注目的是，接种减毒的表达 TAG 表位的单核细胞增生李斯特菌 (LMTAG) 可以阻止肝癌的发展，并导致 TST 群体产生 PD1 异质、TCF1 TOX 和多功能细胞因子生产者。疫苗引发的 TCF1 TST 可以自我更新和分化，将其确立为祖 TST。相比之下，ICB 给药并没有减缓癌症进展或提高 LMTAG 疫苗功效。在临床相关的散发性肝癌模型中，疫苗（而非 ICB）产生了功能性祖细胞 TST 群体并阻止了癌症进展。对于早期癌症或癌症复发风险较高的患者，免疫接种可能是最有效的策略。© 作者（或其雇主）2024。CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Immune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however, only a subset of patients with certain types of cancer achieve durable remission. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term tumor immune reprogramming and arrest cancer progression. We developed a clinically relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumor-specific CD8 T cells (TST) differentiated in mice with early sporadic lesions as compared with late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, impact TST function and liver cancer progression.Mice with a germline floxed allele of the SV40 large T antigen (TAG) undergo spontaneous recombination and activation of the TAG oncogene, leading to rare early cancerous TAG-expressing lesions that inevitably progress to established liver cancer. We assessed the immunophenotype (CD44, PD1, TCF1, and TOX expression) and function (TNFα and IFNγ cytokine production) of tumor/TAG-specific CD8 T cells in mice with early and late liver lesions by flow cytometry. We vaccinated mice, either alone or in combination with ICB, to test whether these immunotherapeutic interventions could stop liver cancer progression and improve survival.In mice with early lesions, a subset of TST were PD1+ TCF1+ TOX- and could produce IFNγ while TST present in mice with late liver cancers were PD1+ TCF1lo/- TOX+ and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitope-expressing Listeria monocytogenes (LMTAG) blocked liver cancer development and led to a population of TST that were PD1-heterogeneous, TCF1+ TOX- and polyfunctional cytokine producers. Vaccine-elicited TCF1+TST could self-renew and differentiate, establishing them as progenitor TST. In contrast, ICB administration did not slow cancer progression or improve LMTAG vaccine efficacy.Vaccination, but not ICB, generated a population of functional progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. In patients with early cancers or at high risk of cancer recurrence, immunization may be the most effective strategy.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.