Chimeric antigen receptors (CAR) utilize costimulatory domains to enhance anti-tumor efficacy. However, it is unclear which costimulatory domain is preferable. Therefore, the intracellular domains of CD28, Dap10, 41BB, GITR, ICOS, or OX40 were compared in a murine chimeric PD1 (chPD1) receptor that targets tumor-associated PD1 ligands. Upon antigen restimulation, T cells expressing chPD1-CD28 receptors had reduced lytic capacity. While most of the chPD1 T cell receptors secreted pro-inflammatory (IFNγ, TNFα, IL-2, GM-CSF, IL-17, and IL-21) and anti-inflammatory cytokines (IL-10), chPD1-Dap10 did not secrete IL-10. Furthermore, chPD1-Dap10 and -41BB receptors induced a memory precursor phenotype, had enhanced persistence in vivo, and superior therapeutic efficacy in murine models of T cell lymphoma and melanoma compared to chPD1-CD28 or chPD1-GITR expressing T cells. Therefore, each costimulatory domain induces differential effects in CAR-expressing T cells and inclusion of Dap10 or 4-1BB costimulatory domains may induce a preferential cytokine profile and differentiation for cancer therapy.

中文翻译：

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chPD1受体中包含Dap10或4-1BB共刺激域可增强T细胞在淋巴瘤和黑色素瘤小鼠模型中的抗肿瘤功效。

嵌合抗原受体（CAR）利用共刺激域来增强抗肿瘤功效。但是，尚不清楚哪个共刺激域是更可取的。因此，在靶向肿瘤相关PD1配体的鼠类嵌合PD1（chPD1）受体中比较了CD28，Dap10、41BB，GITR，ICOS或OX40的细胞内结构域。抗原再刺激后，表达chPD1-CD28受体的T细胞的裂解能力降低。虽然大多数chPD1 T细胞受体分泌促炎性因子（IFNγ，TNFα，IL-2，GM-CSF，IL-17和IL-21）和抗炎性细胞因子（IL-10），但chPD1-Dap10却不分泌分泌IL-10。此外，chPD1-Dap10和-41BB受体诱导记忆前体表型，在体内的持久性增强，与表达chPD1-CD28或chPD1-GITR的T细胞相比，在T细胞淋巴瘤和黑色素瘤小鼠模型中具有更高的治疗效果。因此，每个共刺激结构域在表达CAR的T细胞中诱导不同的作用，Dap10或4-1BB共刺激域的包含可能诱导癌症治疗的优先细胞因子谱和分化。