Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Immunother Cancer. 2023 Jul;11(7). doi: 10.1136/jitc-2023-007198.
Cancer immunotherapies are generally effective in patients whose tumors contain a priori primed T-cells reactive to tumor antigens (TA). One approach to prime TA-reactive T-cells is to administer immunostimulatory molecules, cells, or pathogens directly to the tumor site, that is, in situ vaccination (ISV). We recently described an ISV using Flt3L to expand and recruit dendritic cells (DC), radiotherapy to load DC with TA, and pattern recognition receptor agonists (PRRa) to activate TA-loaded DC. While ISV trials using PRRa have yielded systemic tumor regressions, the optimal method to activate DCs is unknown.
To discover optimal DC activators and increase access to clinical grade reagents, we assessed whether viral or bacterial components found in common pathogen vaccines are an effective source of (). Using deep profiling (155-metric) of naPRRa immunomodulatory effects and gene editing of specific PRR, we defined specific signatures and molecular mechanisms by which naPRRa potentiate T-cell priming.
We observed that vaccine naPRRa can be even more potent in activating Flt3L-expanded murine and human DCs than synthetic PRRa, promoting cross-priming of TA-reactive T-cells. We developed a mechanistically diverse naPRRa combination (BCG, PedvaxHIB, Rabies) and noted more potent T-cell cross-priming than with any single naPRRa. The naPRRa triplet-as part of Flt3L-primed ISV-induced greater intratumoral CD8 T-cell infiltration, T-cells reactive to a newly defined tumorous neoantigen, durable tumor regressions.
This work provides rationale for the translation of pathogen vaccines as FDA-approved clinical-grade DC activators which could be exploited as immune-stimulants for early phase trials.
癌症免疫疗法在那些肿瘤中预先存在对肿瘤抗原（TA）有反应的 T 细胞的患者中通常是有效的。一种产生 TA 反应性 T 细胞的方法是将免疫刺激性分子、细胞或病原体直接施用于肿瘤部位，即原位疫苗接种（ISV）。我们最近描述了一种使用 Flt3L 来扩增和募集树突状细胞（DC）、放射治疗使 DC 负载 TA 以及模式识别受体激动剂（PRRa）来激活负载 TA 的 DC 的 ISV。虽然使用 PRRa 的 ISV 试验已经产生了全身肿瘤消退，但激活 DC 的最佳方法尚不清楚。
为了发现最佳的 DC 激活剂并增加获得临床级试剂的机会，我们评估了常见病原体疫苗中发现的病毒或细菌成分是否是（）的有效来源。通过对 naPRRa 免疫调节作用的深度分析（155 个指标）和对特定 PRR 的基因编辑，我们定义了特定的特征和分子机制，naPRRa 通过这些特征和分子机制增强 T 细胞的启动。
我们观察到，疫苗 naPRRa 可以比合成 PRRa 更有效地激活 Flt3L 扩增的鼠类和人类 DC，促进 TA 反应性 T 细胞的交叉启动。我们开发了一种机制上多样化的 naPRRa 组合（BCG、PedvaxHIB、狂犬病），并注意到与任何单一 naPRRa 相比，其具有更强的 T 细胞交叉启动作用。naPRRa 三联体——作为 Flt3L 启动的 ISV 的一部分——诱导了更大的肿瘤内 CD8 T 细胞浸润、对新定义的肿瘤新生抗原有反应的 T 细胞、持久的肿瘤消退。
这项工作为将病原体疫苗转化为 FDA 批准的临床级 DC 激活剂提供了依据，这些激活剂可以作为早期临床试验的免疫刺激剂加以利用。
