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Abstract
The vast majority of cancer-related deaths are due to metastasis, a process that requires evasion of the host immune system. In addition, a significant percentage of cancer patients do not benefit from our current immunotherapy arsenal due to either primary or secondary immunotherapy resistance. Importantly, select subsets of dendritic cells (DCs) have been shown to be indispensable for generating responses to checkpoint inhibitor immunotherapy. These observations are consistent with the critical role of DCs in antigen cross-presentation and the generation of effective anti-tumor immunity. Therefore, the evolution of efficient tumor-extrinsic mechanisms to modulate DCs is expected to be a potent strategy to escape immunosurveillance and various immunotherapy strategies. Despite this critical role, little is known regarding the methods by which cancers subvert DC function. Herein, we focus on those select mechanisms utilized by developing cancers to co-opt and tolerize local DC populations. We discuss the reported mechanisms utilized by cancers to induce DC tolerization in the tumor microenvironment, describing various parallels between the evolution of these mechanisms and the process of mesenchymal transformation involved in tumorigenesis and metastasis, and we highlight strategies to reverse these mechanisms in order to enhance the efficacy of the currently available checkpoint inhibitor immunotherapies.
Highlights
During tumorigenesis, the process of malignant transformation occurs concurrently with evasion of the host immune system [1, 2]
As the field of immuno-oncology has been primarily focused on directly enhancing the activation of effector T cells, the process of tumor-mediated dendritic cells (DCs) tolerization is comprised of many unexplored opportunities for therapeutically enhancing anti-tumor immunity at earlier stages of the tumor immunity cycle
In pancreatic ductal adenocarcinoma (PDAC) models, PDAC exosomes were found to carry macrophage migration inhibitory factor (MIF), which induces TGF-β signaling in Kupffer cells in the liver resulting in extracellular matrix (ECM) remodeling, a recruitment of bone marrow-derived macrophages and increased metastasis
Summary
The process of malignant transformation occurs concurrently with evasion of the host immune system [1, 2]. The ability of tumors to evolve mechanisms to manipulate their local immune microenvironment is a key component of metastatic progression to distant tissue sites Given their critical role in orchestrating tumor-targeted immune responses, cancers facilitate their escape from immune recognition and subsequent progression by subverting the functions of antigen presenting cells (APCs) known as dendritic cells (DCs). This process of DC tolerization involves the genetic reprogramming of DCs to disable immune recognition of developing malignancies [3,4,5,6]. We review the processes by which cancers actively drive DC tolerization, how these mechanisms may influence responses to modern immunotherapy, and how these processes can be therapeutically manipulated to improve patient outcomes
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