肿瘤细胞治疗研究
英文原题：Exploiting viral infection/vaccination to focus high-affinity T cell populations into tumors using oncolytic viro-immunotherapy.
免疫耐受限制了针对自身肿瘤相关抗原（TAA）具有显著亲和力的 T 细胞数量，从而因无法产生高亲和力抗肿瘤 T 细胞群而制约了肿瘤免疫治疗的成功。
免疫耐受会限制具有显著自体肿瘤相关抗原（TAA）亲和力的 T 细胞数量，因此难以产生高亲和力抗肿瘤 T 细胞群体，限制癌症免疫治疗成功。相反，病毒感染或疫苗接种可启动并扩增针对病毒抗原的高亲和力效应和记忆 T 细胞。本文显示，可利用人群中既存的抗病毒记忆应答，通过溶瘤病毒（OV）或 CAR 介导递送与 TAA 无关的病毒抗原，将高亲和力免疫优势 T 细胞应答聚焦至肿瘤。异源初免后以 OV 加强免疫，使用 SARS-CoV-2 膜蛋白或刺突蛋白（S）作为疫苗/肿瘤聚焦 T 细胞靶点，均可实现依赖 CD8⁺ T 细胞的肿瘤治愈，并伴随针对 TAA 的表位扩展。研究还显示，即使在预先免疫的小鼠中，CAR-T 也可将表达 SARS-CoV-2 抗原的载体经全身递送至肿瘤。最后，S 特异性 CAR-T 可通过 S 蛋白疫苗在体内加强，从而提高抗肿瘤活性和持久性。因此，当缺乏高亲和力抗肿瘤 T 细胞时，利用 OV 介导的免疫原递送，在肿瘤内增强既存感染或疫苗诱导的 T 细胞群体，可作为具有治疗价值的替代策略。
Immune tolerance restricts the number of T cells with significant affinity for self-tumor-associated antigens (TAAs), thereby limiting successful cancer immunotherapy through an inability to generate populations of high-affinity anti-tumor T cells. In contrast, viral infection/vaccination primes and expands high-affinity effector and memory T cells against viral antigens. We show here that it is possible to exploit population-wide preexisting, anti-viral memory recall responses against SARS-CoV-2 antigens to focus a high-affinity, immunodominant T cell response into tumors by oncolytic virus (OV)-mediated or chimeric antigen receptor (CAR)-mediated delivery of viral antigens that are not themselves related to TAAs. Heterologous prime and OV/boost led to CD8 + T cell-dependent tumor cures using either SARS-CoV-2 Mem or Spike (S) proteins as vaccinating/tumor-focusing T cell targets, associated with epitope spreading against TAAs. We also show that CAR-T cells carry SARS-CoV-2 antigen-expressing vectors systemically to tumors even in pre-immune mice. Finally, S-specific CAR-T cells could be boosted in vivo with S protein vaccines to enhance anti-tumor activity and persistence. Thus, where high affinity anti-tumor T cells are not available, boosting preexisting infection- or vaccination-induced T cell populations within tumors using OV-mediated immunogen delivery provides a therapeutically valuable alternative.
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