Understanding Tricky Cellular and Molecular Interactions in Pancreatic Tumor Microenvironment: New Food for Thought

Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents 90% of all pancreatic cancer cases and shows a high mortality rate among all solid tumors. PDAC is often associated with poor prognosis, due to the late diagnosis that leads to metastasis development, and limited efficacy of available treatments. The tumor microenvironment (TME) represents a reliable source of novel targets for therapy, and even if many of the biological interactions among stromal, immune, and cancer cells that populate the TME have been studied, much more needs to be clarified. The great limitation in the efficacy of current standard chemoterapy is due to both the dense fibrotic inaccessible TME barrier surrounding cancer cells and the immunological evolution from a tumor-suppressor to an immunosuppressive environment. Nevertheless, combinatorial therapies may prove more effective at overcoming resistance mechanisms and achieving tumor cell killing. To achieve this result, a deeper understanding of the pathological mechanisms driving tumor progression and immune escape is required in order to design rationale-based therapeutic strategies. This review aims to summarize the present knowledge about cellular interactions in the TME, with much attention on immunosuppressive functioning and a specific focus on extracellular matrix (ECM) contribution.

Keywords: ECM; PDAC; TME; immune escape; immunotherapy.

Figure 1

Simplified scheme of stroma-mediated interaction in PDAC. Cancer-associated fibroblasts (CAFs) are crucial elements of the pancreatic ductal adenocarcinoma (PDAC) stroma. They include different subtypes: myofibroblastic, inflammatory, and antigen-presenting subtypes. Both cell–cell and paracrine interaction CAFs and PDAC cells are involved in manipulating the stroma. The cancer cells can induce, through transforming growth factor-β (TGFβ) signaling, the surrounding CAFs to adopt a myfibroblastic phenotype. Similarly, cancer cells produce IL-1, reprogramming CAFs to inflammatory CAFs, which, in turn, produce chemokines like IL-6 and sustain cancer growth. Antigen-presenting CAFs, expressing MHC class II molecules, modulate the immune cells in the stroma. Pancreatic stellate cells (PSCs) are mainly responsible for ECM deposition during PDAC, and are also able to modulate the immune response through the production and secretion of cytokines, such as CXCL12 and IL-6, negatively affecting T-cell activity and migration. Adapted from “PDAC histology” by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.

Figure 2

Main strategies to overcome myeloid and Treg-mediated immunosuppression. Dendritic cells or inflammatory macrophages (TAMs M1) sustain the antitumor immune response through antigen presentation. Myeloid-derived suppressor cells (MDSCs), anti-inflammatory tumor-associated macrophages (TAMs M2), and regulatory T (Treg) cells regulate these processes by exploiting inhibitory pathways, thus establishing an immunosuppressive tumor microenvironment. Some of the most clinically relevant therapeutic strategies available to target those pathways are reported. Created with BioRender.com.