Targeting the tumor microenvironment in pancreatic ductal adenocarcinoma

Abstract

Introduction: The dismally slow improvement in patient survival over the years for pancreatic cancer patients is mainly due to two factors: the late diagnosis, at which point the disease is spread to distant organs; and the fact that tumor cells are surrounded by a dense, highly immunosuppressive microenvironment. The tumor microenvironment not only shields pancreatic cancer cells from chemotherapy but also leaves it unsusceptible to various immunotherapeutic strategies that have been proven successful in other types of cancer. Areas covered: This review highlights the main components of the pancreatic tumor microenvironment, how they cross-talk with each other to generate stroma and promote tumor growth. Additionally, we discuss the most promising treatment targets in the microenvironment whose modulation can be robustly tested in combination with standard of care chemotherapy. Currently, active clinical trials for pancreatic cancer involving components of the microenvironment are also listed. Expert opinion: Although immunotherapeutic approaches involving checkpoint inhibition are being pursued enthusiastically, there is still more work to be done with several other emerging immune targets that could provide therapeutic benefit.

Keywords: Pancreatic cancer; fibroblasts; myeloid derived suppressor cells; stellate cells; tumor microenvironment; tumor-associated macrophages.

Figure 1:. Pancreatic tumor microenvironment and cross-talk within its components.

Schematic depicting pancreatic acinar cells progressing through precancerous lesion types to PDAC and their interaction with different stromal cell types. Activated stellate cells and transformed acinar cells undergoing acinar to ductal metaplasia (ADM), release cytokines that recruit M1 macrophages, generating an inflammatory environment. Fibroblasts and PanIN cells release factors that promote polarization of M1 macrophages to pro-tumor M2 macrophages. Activated stellate cells and fibroblasts also release proteins that make up a dense and fibrous extracellular matrix, a hallmark of pancreatic cancer. Tumor cells release HIF-1α that can attract MDSCs. MDSCs along with regulatory T cells, immunosuppressive factors released by TAMs/M2 macrophages and suppressive signals from tumor cells cause the suppression of effector T cells.

Figure 2:. Therapeutic targets in the tumor microenvironment.

Several components outside and within the microenvironment contribute to effector T cell suppression. Dendritic cells in the regional lymph nodes expressing CD80/86 on the surface, bind to CTLA-4 present on the T cells blocking appropriate priming for T cells. This can be targeted by anti-CTLA-4 antibodies. Tumor cells express the ligand PD-L1, which can also render the effector T cells inhibited and unable to perform effector functions once bound to the PD1 receptor on T cells. This can be targeted by anti-PD1 and anti-PD-L1 antibodies. Regulatory T cells (Tregs), whose primary function is to curtail effector T cell function, are heavily recruited in the microenvironment by GM-CSF. GVAX in combination with chemotherapeutics leads to reduced Treg recruitment and enrichment of effector T cells. T cell suppression can also be reduced by targeting MDSCs via COX-2 inhibition, targeting the CSF-1 receptor or by using triterpenoids that are shown to reduce MDSCs in the tumors by downregulating ROS production. Alternatively activated or M2 macrophages are one of the major orchestrators of the immunosuppressive environment, making them an important target. M2 polarization can be caused by IL-13, making IL-13 neutralizing antibodies a potential therapeutic. Pomalidomide treatment can also reduce M1 to M2 polarization. Lastly, the dense stroma in the tumor poses an enormous challenge in PDAC therapy and its depletion is essential. Targeting the stromal proteins by MMP inhibition and hyaluronic acid depletion are promising strategies for better delivery of any therapy including chemotherapeutic drugs.