综合免疫表型分析揭示了抗 PD-1 敏感和耐药同源小鼠模型中不同的肿瘤微环境改变

The advent of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway has revolutionized cancer treatment, resulting in improved clinical outcomes.

However, resistance remains a critical challenge. This study aimed to comparatively elucidate immunophenotypic changes in syngeneic mouse models sensitive (MC-38) or resistant (LLC1) to anti-PD-1 monoclonal antibody (mAb) treatment. In the sensitive MC-38 model, anti-PD-1 therapy increased dendritic cells (DCs) and macrophages, while decreasing myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment.

Enhanced expression of antigen presentation molecules (MHC I/II) and costimulatory molecules (CD80/CD86) was observed on tumor-associated DCs and macrophages. Tumor-infiltrating CD4 + T, CD8 + T, regulatory T, NK, and NKT cells also significantly increased.

Importantly, treatment boosted lymphocyte cytotoxic potential, with perforin identified as a key marker of efficacy.

Notably, perforin expression in CD4 + T and NKT cells strongly negatively correlated with tumor volume. In contrast, the resistant LLC1 model exhibited minimal immunophenotypic changes upon treatment.

These findings highlight critical immune modifications induced by anti-PD-1 therapy, particularly the role of perforin, and the DC/MDSC ratio in predicting therapeutic outcomes. This research offers valuable insights into potential predictive biomarkers and informs strategies to overcome resistance, emphasizing the complex interplay between anti-PD-1 treatment and the tumor microenvironment, ultimately aiming to improve immunotherapy response rates.