PTC596 联合 PD1 阻断在肝细胞癌中增强的抗肿瘤疗效

PTC596 has been studied in advanced solid tumors in clinical trials.

However, the effects of PTC596 alone or in combination with programmed cell death protein-1 (PD1) blockade in hepatocellular carcinoma (HCC) remain unclear. Subcutaneous tumor models in both Balb/c and C57BL/6 mice were used to evaluate the effects of PTC596 alone or combined with an anti-PD1 antibody (anti-PD1) on tumor growth control, survival, and tumor-infiltrating immune cells, and the underlying mechanism was investigated by immunofluorescence, flow cytometry, RNA sequencing and immunohistochemistry.

We found PTC596 not only killed HCC cells in vitro but also controlled H22 and Hepa1-6 tumor growth in vivo. PTC596 promoted the infiltration of CD8+ T-cells in H22 and Hepa1-6 models.

Importantly, combination therapy (PTC596 plus anti-PD1) showed superior antitumor efficacy and prolonged mouse survival.

Moreover, combination therapy induced robust antitumor immune activity by activating mature dendritic cells, CD8+ T-cells, natural killer cells, inflammatory monocytes, and total macrophages, while suppressing the infiltration of B cells and M2-type macrophages. RNA sequencing confirmed that the antitumor effects of PTC596 alone or plus anti-PD1, relied on the regulation of inflammation- and immune-associated pathways.

Furthermore, combination therapy induced long-term immunological memory in 'cured' mice, as these mice were unaffected by tumor rechallenge after the original tumors were eliminated.

Therefore, PTC596 is not only an effective antitumor drug for HCC but also supports the formation of a favorable tumor microenvironment that enhances the effect of PD1 blockade.

This study supports that PTC596 combined with PD1 blockade could be a promising strategy for HCC.