Targeting the Tumor Microenvironment for Pancreatic Ductal Adenocarcinoma Therapy

Yi-Fan Zhang; Shu-Heng Jiang; Li-Peng Hu; Pei-Qi Huang; Xu Wang; Jun Li; Xue-Li Zhang; Hui-Zhen Nie; Zhi-Gang Zhang


Chin Clin Oncol. 2019;8(2) 

In This Article


Because of the difficulties in diagnosing PDAC, only 15% to 20% of PDAC patients can be treated with resection procedures.[75] Furthermore, the results of chemotherapy and radiotherapy are poor; therefore, new therapy options are necessary.

To treat PDAC, immunotherapy has been developed to target immune molecules, such as IL-2, to blocking immune checkpoints.[76,77] The targeting of immune molecules (PD-1 and PD-L1) to disrupt immune checkpoints and treat tumors has been applied to metastatic melanoma, and this strategy is on track to replace chemotherapy and become a mainstream treatment.[78,79] However, in PDAC, the treatment is not as straightforward as the treatment of melanoma. The CAFs that compose the ECM have suppressive immune functions and must be eliminated before a T cell response can ensue. CAFs secrete CCL2 and CXCL2 to recruit myeloid cells and synergistically suppress the immune response; clinical research has started targeting these chemokines and/or its receptors.[80]

Vaccine immunotherapy for PDAC is currently being investigated, and this method has two steps that are designed to treat PDAC. The low number of lymphocytes and high number of immunosuppressive cells are responsible for the poor immune response of PDAC.[81] The first step aims to accumulate lymphocytes, which secrete interferon gamma and other immune elements that induce tumor cells and immune cells to express a high level of PD-L1/PD-1.[82,83] The second step aims to inhibit the PD-L1/PD-1 signaling pathway to increase lymphocyte proliferation and function.[41] The vaccine therapy method is expected to increase the number of immune cells and enhance their function to prevent tumor growth.

Because of the desmoplastic changes of the ECM, the treatment of PDAC has become a huge challenge; the components of the PDAC ECM, including CAFs, collagen, proteoglycan, and hyaluronan, are targeted for treatment. Some labs have begun trying to stop the detrimental collaboration of CAFs and tumor cells through drugs, and the use of 4-methylumbelliferone attempted to solve the hyaluronan problem.[84,85] In this clinic, studies have tested the safety and efficacy of the Nab-paclitaxel-gemcitabine method, and because this method has low toxicity, it is recommended as a first-line therapy for patients with metastatic disease.[86,87]

The TME stromal factors lead to PDAC being more complicated, immunosuppressive and resistant to drugs. Recent research has focused not only on the factors themselves but also on the downstream or upstream factors. KRAS, one of the most potent of all human oncogenes, regretfully cannot be effectively targeted as a drug because of its smooth surface.[88,89] To target KRAS, microRNA was designed to decrease KRAS expression at the RNA level.[90] The TGF-β, TGF-βR and TGF-β pathway activation protein SMAD commonly has mutations in pancreatic cancer. To target the TGF-β pathway, siRNA and negatively regular protein SnoN were tested for their ability to decrease cell proliferation as a possible targeted therapy for TGF-β.[91,92] SHH binds to the PTCH1 receptor and regulates the Smoothened protein (SMO) and its downstream pathways; treating tumors with inhibitors of the SMO receptor in combination with gemcitabine decreases desmoplasia and collagen deposition in TME and enhances the gemcitabine concentration, resulting in increased overall survival in mice.[93] However, the results of the SMO antagonist in clinical research disappointedly demonstrated no significant results.[94]

Apart from therapy methods, many medicines and therapy methods have been investigated to conquer this deadly cancer. Tamoxifen, a candidate for PDAC therapy, remodels TME and reduces the tumor cell survival rate by hypoxia-inducible factor-1 alpha.[95] A series of antibodies for immune cell inhibitors that target the immunosuppressive TME of PDAC have been tested.[96] Urolithin A, which targets the PI3K/AKT/mTOR pathway, has been investigated as a potential therapeutic agent in recent research.[97]