Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer

Abstract

Immunotherapies have shown benefits across a range of human cancers, but not pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that the immunosuppressive tumor microenvironment (TME) constitutes an important roadblock to their efficacy. The landscape of the TME differs substantially across PDAC subtypes, indicating context-specific principles of immunosuppression. In this review, we discuss how PDAC cells, the local TME, and systemic host and environmental factors drive immunosuppression in context. We argue that unraveling the mechanistic drivers of the context-specific modes of immunosuppression will open new possibilities to target PDAC more efficiently by using multimodal (immuno)therapeutic interventions. Significance: Immunosuppression is an almost universal hallmark of pancreatic cancer, although this tumor entity is highly heterogeneous across its different subtypes and phenotypes. Here, we provide evidence that the diverse TME of pancreatic cancer is a central executor of various different context-dependent modes of immunosuppression, and discuss key challenges and novel opportunities to uncover, functionalize, and target the central drivers and functional nodes of immunosuppression for therapeutic exploitation.

Classification molecular subtypes of hepatocellular carcinoma based on PRMT-related genes

“…Despite great advances for immunotherapy in cancers, the majority of patients relapse or fail to response to immunotherapy due to insufficient immune response against tumors or suppressive tumor microenvironment (TME) (Falcomatà et al, 2023). PRMTs have been elucidated as key factor in tumor immunosurveillance of TME (Dai et al, 2022;Fedoriw et al, 2022).…”

NETosis: Sculpting tumor metastasis and immunotherapy

“…Cancer represents a complex ecosystem composed of tumor cells and numerous nontumor cells, embedded within remarkably altered extracellular matrix 126,127 . The TME comprises distinct immune cell populations, cancer‐associated fibroblasts (CAFs), endothelial cells, pericytes, additional tissue‐resident cell populations, etc 128 The cellular compositions and functional status of the TME enable to differ extensively dependent upon metastatic organs, tumor intrinsic characteristics, tumor staging, patient features, etc. Apart from cancer metastasis, 129 accumulated evidence has demonstrated that uncontrolled or excessive formation of NETs exerts manifold functions in anticancer immunity through interacting with the TME components 130,131 .…”

Advancing Cancer Treatment Through Nanotechnology Driven Immunotherapy for Pancreatic Cancer

“…Furthermore, the TME plays a crucial role in tumorigenesis, influencing tumor growth, progression, and response to therapy . Particularly, the TME in PDAC exhibits immunosuppressive properties, leading to impaired antitumor immune responses . In addition, the dense desmoplastic stroma is composed of activated pancreatic stellate cells (PSCs), fibroblasts, immune cells, and extracellular matrix (ECM) components .…”

“…44 Particularly, the TME in PDAC exhibits immunosuppressive properties, leading to impaired antitumor immune responses. 45 In addition, the dense desmoplastic stroma is composed of activated pancreatic stellate cells (PSCs), fibroblasts, immune cells, and extracellular matrix (ECM) components. 46 This stromal reaction contributes to tumor growth, invasion, and immune evasion.…”