Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.

Keywords: cancer therapy; fibroblasts; immune cells; pancreatic ductal adenocarcinoma; tumor microenvironment; tumor stroma.

Figure 1

PDAC microenvironment and the cellular interplay. Pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous in both cellular and acellular components. The tumor cells themselves are varied in mutation/gene expression profile, which manipulates the surrounding fibroblasts and immune cells. In turn, the tumor microenvironment components interact with each other and with tumor cells in a pro-tumor support fashion. The major interplay in PDAC includes (i) CAFs activation which leads to creating a desmoplastic stroma, (ii) metabolic reprogramming, (iii) immunological transformation, and (iv) metastasis initiating events in early stages of tumor development. Treg = regulatory T cell, Teff = effector T cell, PaSC = Pancreatic stellate cells, PDAC = pancreatic ductal adenocarcinoma, EMC = extracellular matrix, myCAF = myofibroplastic cancer associated fibroblast, iCAF = inflammatory cancer associated fibroblast. Figure made in BioRender.

Figure 2

Neoplastic cells and ECM targeting approaches in PDAC treatment. Because of its large contribution to tumor development and treatment resistance, the heterogeneity of tumor cells, mutations, and ECM of PDAC are also attractive targets for therapeutic development. Targeting the KRAS protein and its upstream and downstream signaling are some of the most potential targets for drug development and are under investigation in several trials. Besides that, the therapeutic approaches for eliminating cancer stem cells in PDAC focus on targeting particular major signaling pathways by small molecules or targeting core genetic regulators, such as microRNA, as listed in the boxes. The ECM consists of collagens, fibronectin, and other proteins that can be targeted, together with other therapeutic strategies. PaSC = pancreatic stellate cells, PDAC = pancreatic ductal adenocarcinoma, EMC = extracellular matrix, myCAF = myofibroplastic cancer associated fibroblast, iCAF = inflammatory cancer associated fibroblast. Figure made in BioRender.

Figure 3

Immunotherapies to treat PDAC. There are several proposed strategies to target immunological aspects of PDAC which are (i) cancer vaccines, (ii) targeting immunosuppressive mechanism by immune checkpoint blockage therapy, and (iii) adoptive cell transfer which are comprised of NK, Cytotoxic lymphocyte, and CAR-T therapies. PDAC = pancreatic ductal adenocarcinoma, PD-1 = programmed cell death protein 1, CTLA-4 = cytotoxic T lymphocyte associated protein 4, TCR = T cell receptor, Treg = regulatory T cell, MDSC = myeloid derived suppressor cell, M2 = Tumor associated M2 macrophage, N2 = tumor associated N1 neutrophil, MHC = major histocompatibility complex, CAR = chimeric antigen receptor. Figure made in BioRender.