TGF-β3 promotes vascular normalization of prostate cancer to potentiate immunotherapy and chemotherapy.

BACKGROUND

Prostate cancer (PCa) has previously been established as a cold tumor with highly complex tumor environment. Transforming growth factor (TGF)-β1 plays pro-oncogenic roles in PCa. TGF-β3, another isoform of the TGF-β family, is reported to have different and even opposite regulatory roles to TGF-β1. However, the effect of TGF-β3 in PCa has not been elucidated.

METHODS

TGF-β3 expression and its association with multiple clinicopathological characteristics were analyzed immunohistochemically in human PCa specimens. The antitumor effect of TGF-β3 and its combination with immunochemotherapy was observed by subcutaneous xenograft tumor model. RNA-seq of mouse tumor tissues identified differentially expressed genes (DEGs) that were enriched in vascular biological processes. The angiogenesis effect of TGF-β3 was evaluated using tube formation assay. Hypoxic area, NG2 pericytes, Col IV basement membrane, adhesion molecules and immune cells were analyzed by immunofluorescence. Vascular permeability was measured by Evans blue staining. The flow cytometry was conducted to examine the composition of tumor-infiltrating CD8 T cells.

RESULTS

Low TGF-β3 expression in prostate cancer (PCa) was correlated with higher Gleason scores and pathological T stage. While intratumoral TGF-β3 injection demonstrated antitumor effects in vivo, it did not directly affect PCa cell proliferation, migration or invasion in vitro. GO analysis revealed significant enrichment of DEGs in vascular-related biological process. TGF-β3 treatment normalized tumor vascular architecture and reduced vascular leakage. This vascular normalization upregulated endothelial adhesion molecules and enhanced CD8 T cell infiltration, suppressing tumor growth. Critically, TGF-β3-induced vascular normalization synergized with anti-PD-L1 immunotherapy or paclitaxel chemotherapy, enhancing CD8 T cell or drug infiltration and significantly boosting therapeutic efficacy.

CONCLUSIONS

TGF-β3 potentially acts as a protective factor in PCa by promoting vascular normalization and remodeling of the tumor environment, which facilitates infiltration of CD8 T cells or drugs, significantly enhancing their antitumor effects.