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

The Immune System

Immune cells may affect the composition of pancreatic stroma to affect the progression of PDAC.[29] Recent research reports that prominent overall leukocyte infiltration is associated with increased survival.[30]

The TME and immune system have a close relationship, and a number of interactions between the TME and immune system affect tumor development (Figure 2).[31–36] The T cell immunocytes in particular can recognize the non-self and then remove the invaders. The process of normal cells turning into cancer cells is an example of the self to non-self progression, and T cells can kill the cancer cells. Once the effector T cell activation reaches a threshold, Tregs become activated and release TGF-β and IL-10 immunosuppressive cytokines to negatively regulate T cell function.[37] To develop and proliferate, the cancer cells break this balance between the inhibitors and activation level though abrogating coactivatory signals and augmenting coinhibitory signals, which ultimately heightens anergy and exhaustion.[38]

Figure 2.

Interactions of the immune system, TME factors and pancreatic cancer cells. γδ T cells promote tumor development and block CD8+ and CD4+ T cell infiltration to kill tumor cells. The fibroblasts recruit Bregs by secreting CXCL13, and Bregs secret IL-35, which results in tumor progression. However, fibroblasts block stromal fibroblasts, which then block Treg accumulation and PDAC progression. Pancreatic cancer cells drive macrophages into the TME with CCL2, and macrophages drive tumor growth. Fusobacterium in the PDAC microenvironment were reported to have a relationship with PDAC development, but its mechanism is not clear. TME, tumor microenvironment; PDAC, pancreatic ductal adenocarcinoma.

In a healthy body, the action of T cells through major histocompatibility complex (MHC) engagement is regulated by stimulating signals and inhibitory signals, which are referred to as immune checkpoints. To breakdown and benefit from this regulation, tumor cells expand the coinhibitory signal and abolish the coactivatory signal.[38]

Research has focused on cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), two factors that function on immune checkpoint inhibitors. The CLTA-4 pathway is activated by tumor cells to downregulate the CD28 costimulatory receptor, an important ligand for transmitting secondary signals for T cell activation and increasing the threshold of T cell activation, resulting in immunosuppression.[39] Regulated by FUBP1, IRF1, cytokines, etc., the cancer cells upregulate PD-1, which binds to PD-1 receptors on T cells to cause a loss of T cell function, cell anergy, or cell death.[40–43] In addition to CTLA-4 and PD-1, new targets have been identified. Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, affects B-cell and macrophage-mediated T cell suppression in pancreatic adenocarcinomas, inhibits T cell antitumor function and improves the PDAC response to chemotherapy.[44] The inhibitor of receptor tyrosine kinase Axl can be established as a preclinical mechanistic target to improve the overall survival rate.[45] Dickkopf-3 (DKK3) is a potential therapeutic target as well.[46]

Interleukins (ILs) are secreted by many kinds of cells that participate in immune regulation, hematopoiesis and inflammation. IL-6 is one of IL family members produced by pancreatic satellite cells (PSCs) and PDAC cells and is associated with tumor growth, survival, metastasis, chemoresistance, etc..[47,48] IL-6 can activate MDSCs via the JAK/STAT3 pathway, and a high MDSC level indicates a high risk of a poor patient outcome.[49] The STAT3 pathway and NRF2 pathway, which are induced by STAT3, promote epithelial-mesenchymal transition (EMT) in PDAC.[39,50] The IL-6/JAK/STAT3/NREF2 pathway benefits tumor development and thus targeting this pathway may inhibit tumor growth and metastasis to prolong patient survival. After EMT marker expression, IL-6 may be associated with a number of activation factors for the macrophage phenotype switch.[51]