The Role of Tumor Microenvironment in Pancreatic Cancer Immunotherapy: Current Status and Future Perspectives

Abstract

Pancreatic cancer comprises different subtypes, where most cases include ductal adenocarcinoma (PDAC). It is one of the deadliest tumor types, with a poor prognosis. In the majority of patients, the disease has already spread by the time of diagnosis, making full recovery unlikely and increasing mortality risk. Despite developments in its detection and management, including chemotherapy, radiotherapy, and targeted therapies as well as advances in immunotherapy, only in about 13% of PDAC patients does the overall survival exceed 5 years. This may be attributed, at least in part, to the highly desmoplastic tumor microenvironment (TME) that acts as a barrier limiting perfusion, drug delivery, and immune cell infiltration and contributes to the establishment of immunologically 'cold' conditions. Therefore, there is an urgent need to unravel the complexity of the TME that promotes PDAC progression and decipher the mechanisms of pancreatic tumors' resistance to immunotherapy. In this review, we provide an overview of the major cellular and non-cellular components of PDAC TME, as well as their biological interplays. We also discuss the current state of PDAC therapeutic treatments and focus on ongoing and future immunotherapy efforts and multimodal treatments aiming at remodeling the TME to improve therapeutic efficacy.

Keywords: immunotherapy; pancreatic cancer; tumor microenvironment.

Figure 1

Pancreatic tumor microenvironment remodeling strategies to improve therapeutic efficacy. Uncontrolled proliferation of pancreatic cancer cells within desmoplastic stroma, established by excessive deposition of ECM components such as collagen, hyaluronan, and fibronectin, results in the accumulation of mechanical forces and collapsed blood vessels. As a result, abnormal vascularization and ECM stiffness impair vessel perfusion, tumor oxygenation, and drug delivery. In addition, this hinders the infiltration of cytotoxic immune cells, such as CD8+ T and NK cells, and creates a highly immunosuppressive TME along with the secretion of inflammatory cytokines and chemokines by iCAFs, Tregs cells, MDSCs, Bregs, and M2-type TAMs. ECM remodeling strategies using anti-fibrotic drugs and reprogramming of the immunosuppressive TME using immunomodulatory agents could be used synergistically to reverse this phenomenon. This combinatorial approach could normalize tumor vasculature and enhance vessel perfusion and oxygenation, followed by increased infiltration of CD8+ T and NK cells and a decrease in immunosuppressive Tregs, MDCSs, and iCAFs, as well as polarization of TAMs towards an anti-tumor M1 phenotype. Collectively, these strategies aim to enhance pancreatic anti-tumor immunity and the efficacy of ICBs in combination with chemo- and/or nanotherapy to significantly improve pancreatic cancer immunotherapy and patient outcomes. Created with BioRender.com. TME: tumor microenvironment; ICBs: immune checkpoint blockers; M1 TAMs: M1 type tumor-associated macrophages; M2 TAMs: M2 type tumor-associated macrophages DCs: dendritic cell; MDSCs: myeloid-derived suppressor cells; NK cells: natural killer cells; Treg cells: regulatory T cells; PDAC cells: pancreatic ductal adenocarcinoma cells; myCAFs: myofibroblastic cancer-associated fibroblasts; iCAFs: inflammatory cancer-associated fibroblasts; CD4+ T cells: CD4+ cytotoxic T cells, CD8+ T cells: CD8+ cytotoxic T cells; Breg cells: regulatory B cells.