PIN1 inhibition in combination with immunochemotherapy caused pancreatic tumor regression in vivo.

  • Major Finding: PIN1 inhibition in combination with immunochemotherapy caused pancreatic tumor regression in vivo.

  • Concept: PIN1 inhibition impeded a protumorigenic TME, increasing PD-L1 and gemcitabine transporter levels.

  • Impact: This study highlights the therapeutic potential of combining PIN1 inhibition with immunochemotherapy.


Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that displays a high degree of tumor heterogeneity and inhabits a desmoplastic and immunosuppressive tumor microenvironment (TME). As these factors contribute to resistance against chemotherapy, targeted therapy, and immunotherapy, research has focused on targets that may sensitize tumors to therapeutic agents. Given that inhibition of the unique phosphorylation-specific proline isomerase PIN1, which regulates multiple cancer pathways, was previously suggested to increase response to anticancer therapies, Koikawa and colleagues investigated PIN1 inhibition including using clinically available drugs in PDAC. In multiple mouse models, PIN1 inhibition decreased collagen deposition, cancer-associated fibroblast (CAF) proliferation, and tumor-infiltrating immunosuppressive cells while increasing tumor-infiltrating cytotoxic immune cells. Notably, treatment with a combination of PIN1 inhibition, gemcitabine, and anti–PD-1 led to complete regression in the majority of mice, with no visible residual disease for at least one year. In tissue from patients with PDAC, PIN1 was overexpressed in cancer cells and CAFs, and high PIN1 in both cell types strongly correlated with decreased patient survival. To understand the role of PIN1 in specific cell types, PIN1 was suppressed in patient-derived primary CAFs, revealing that PIN1 inhibition induced a quiescent CAF phenotype and prevented cytokine secretion. Compared with control CAFs that promoted PDAC organoid growth when co-cultured in vitro and co-transplanted in vivo, CAFs with PIN1 inhibition failed to promote tumor growth or fibrosis. In PDAC cells, PIN1 inhibition upregulated ENT1, the nucleoside transporter required for gemcitabine uptake, as well as PD-L1, the ligand whose upregulation can increase anti–PD-1 efficacy, explaining PIN1-mediated sensitization to these agents. Specifically, PIN1 promoted the HIP1R-mediated endocytosis and lysosomal degradation of ENT1 and PD-L1 by acting on the conserved serine-proline site, Ser929, on HIP1R after phosphorylation to promote HIP1R binding to actin. In mice expressing KRASG12D and p53R172H in the pancreas, an aggressive spontaneous PDAC model, PIN1 inhibition plus gemcitabine and anti–PD-1 remodeled the TME and significantly extended survival. In summary, this work highlights the therapeutic potential of targeting PIN1 in combination with immunochemotherapy in pancreatic cancer.

Koikawa K, Kibe S, Suizu F, Sekino N, Kim N, Manz TD, et al. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell 2021 Aug 12 [Epub ahead of print].

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