Targeting the IGF-Axis Potentiates Immunotherapy for Pancreatic Ductal Adenocarcinoma Liver Metastases by Altering the Immunosuppressive Microenvironment.
Masakazu HashimotoJohn David KondaStephanie PerrinoMaria Celia FernandezAndrew M LowyPnina BrodtPublished in: Molecular cancer therapeutics (2021)
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, resistant to chemotherapy and associated with high incidence of liver metastases and poor prognosis. Using murine models of aggressive PDAC, we show here that in mice bearing hepatic metastases, treatment with the IGF-Trap, an inhibitor of type I insulin-like growth factor receptor (IGF-IR) signaling, profoundly altered the local, immunosuppressive tumor microenvironment in the liver, curtailing the recruitment of myeloid-derived suppressor cells, reversing innate immune cell polarization and inhibiting metastatic expansion. Significantly, we found that immunotherapy with anti-PD-1 antibodies also reduced the growth of experimental PDAC liver metastases, and this effect was enhanced when combined with IGF-Trap treatment, resulting in further potentiation of a T-cell response. Our results show that a combinatorial immunotherapy based on dual targeting of the prometastatic immune microenvironment of the liver via IGF blockade, on one hand, and reversing T-cell exhaustion on the other, can provide a significant therapeutic benefit in the management of PDAC metastases.
Keyphrases
- liver metastases
- poor prognosis
- growth hormone
- binding protein
- pi k akt
- long non coding rna
- small cell lung cancer
- signaling pathway
- squamous cell carcinoma
- immune response
- cell cycle arrest
- risk factors
- type diabetes
- locally advanced
- cell death
- radiation therapy
- combination therapy
- metabolic syndrome
- oxidative stress
- rectal cancer
- adipose tissue
- replacement therapy