Targeting heterogeneous tumor microenvironments in pancreatic cancer mouse models of metastasis by TGFß depletion.

ABSTRACT

The dual tumor-suppressive and promoting function of TGFß signaling has made its targeting challenging. We hereby examined the effects of TGFß depletion by AVID200/BMS-986416(TGFß-TRAP), a TGFß ligand trap, on the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) murine models with different organ-specific metastasis. Our study demonstrated that TGFß-TRAP potentiates the efficacy of anti-PD-1 in a PDAC orthotopic murine model with liver metastasis tropism, significantly reducing liver metastases. We further demonstrated the heterogeneous response of cytotoxic effector T-cells to combination TGFß-TRAP and anti-PD-1 treatment across several tumor models. Single-nuclear RNA-sequencing suggested that TGFß-TRAP modulates cancer associated fibroblast (CAF) heterogeneity and suppresses neutrophil degranulation and CD4+ T-cell response to neutrophil degranulation. Ligand-receptor analysis indicated that TGFß-TRAP may modulate the CCL5-CCR5 axis as well as co-stimulatory and checkpoint signaling from CAFs and myeloid cells. Notably, the most highly expressed ligands of CCR5 shifted from the immunosuppressive CCL5 to CCL7 and CCL8, which may mediate the immune agonist activity of CCR5 following TGFß-TRAP and anti-PD-1 combination treatment. This study suggested that TGFß depletion modulates CAF heterogeneity and potentially reprograms CAFs and myeloid cells into anti-tumor immune agonists in PDAC, supporting the validation of such effects in human specimen.