过继性 CD8(+)T 细胞移植联合脂质体免疫治疗药物以对抗免疫抑制性肿瘤微环境并增强黑色素瘤治疗

The immunosuppressive tumor microenvironment has become a formidable obstacle to the treatment of tumors using adoptive T cell therapy, in particular solid tumors. For the purposes of addressing this issue, effector OT-1 CD8 + T cells conjugated with liposomal immune regulators (CD8-T-LP-CpG/CD8-T-LP-BMS-202) were developed. An anionic liposome formulation was employed to avoid T cell aggregation and prevent unfavorable side-effects. The inclusion of EGCG in the LP-CpG formulation facilitated the formation of compact complexes with poly lysine (PLL) and is thus expected to increase the stability.

CD8-T-LP-CpG administered with a median dose of CpG (20 μg per mouse) markedly reduced the frequency of tumor infiltrating polymorphonuclear leukocyte myeloid-derived suppressor cells (PMN-MDSCs) (20-folds), M2-like macrophages (8-folds), regulatory T-cells (Treg) (2. 7-folds), and consequently increased the frequency of cytotoxic CD8 + T cells in tumor-infiltrating lymphocytes (TILs) (2-folds) and splenic effector memory CD8 + T cells (3-folds) relative to the phosphate buffered saline (PBS) control group.

Furthermore, the absolute number of tumor infiltrating lymphocyte subtypes altered followed a consistent trend. The difference remained significant compared to the OT-1 CD8 + T cells and the drug-loaded liposome combination group. According to in vivo imaging of CD8-T-LP-DiD, we assumed that the improvement in regulation of the tumor microenvironment of LP-CpG/LP-BMS-202 was attributed to the enhanced drug transportation to the tumor site aided by tumor-specific OT-1 CD8 + T cells.

In addition, CD8-T-LP-BMS-202 administered with a low dose of BMS-202 (1. 5 mg per kg body weight) exerted a dramatically improved therapeutic effect by reducing the tumor infiltrating PMN-MDSCs and M2-like macrophages and the corresponding promoted cytotoxic CD8 + T cell recruitment in the TILs and effector memory CD8 + T cells mediated anti-tumor immunity. In summary, immune therapy drugs backpacked onto adoptive T cell therapy provides a feasible strategy to improve the therapeutic effect and could result in future clinical translation.