Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion.
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2019-01
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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.
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DeVito, Nicholas C, Michael P Plebanek, Bala Theivanthiran and Brent A Hanks (2019). Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion. Frontiers in immunology, 10. p. 2876. 10.3389/fimmu.2019.02876 Retrieved from https://hdl.handle.net/10161/26407.
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Nicholas Christian DeVito
I am an Assistant Professor of Medical Oncology who primarily treats patients with colon cancer and gastroesophageal cancers. My laboratory and translational research is focused on tumor immune evasion and immunotherapy, particularly in the setting of metastasis. This work has led to a specific interest in tumor-mediated development of dendritic cell tolerance and suppressive myeloid populations. The ultimate goal of this research is to create biomarker-directed immunotherapies for advanced gastrointestinal cancers.
Brent A. Hanks
We are interested in understanding the mechanisms that cancers have evolved to suppress the generation of tumor antigen-specific immune responses and how this knowledge can be exploited for the development of novel and more effective cancer immunotherapy strategies. This work involves the utilization of both autochthonous transgenic tumor model systems as well as clinical specimens to develop novel strategies to enhance the efficacy of immunotherapies while also developing predictive biomarkers to better guide the management of cancer patients with these agents. We strive to translate our understanding of the fundamental biochemical and metabolic pathways within the tumor microenvironment that are critical for driving immune evasion and resistance into early phase clinical trial testing.
Our work utilizes a variety of techniques and methodologies that span the breadth of basic biological research. This work integrates studies based on both 1) transgenic mouse tumor models that are monitored using bioluminescence and micro-CT imaging and 2) a variety of clinical specimens.
Our current areas of focus include:
- Investigating mechanisms of adaptive or acquired immunotherapy resistance in cancer
- Studying the relationship between EMT pathways and immunotherapy resistance.
- Elucidating mechanisms of dendritic cell tolerization in the tumor microenvironment and how these processes may contribute to immunotherapy resistance
- Development of novel pharmacologic and genetic strategies to overcome immunotherapy resistance
- Investigating mechanisms contributing to select immunotherapy-associated toxicities
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