Besides cell intrinsic damage to DNA, radiation (RT) can have systemic effects on the immune system. As such, recent evidence indicates that the efficacy of immune checkpoint blockade (ICB) for cancer can be improved by combination strategies that utilized both RT and ICB. However, our understanding of the pathways that RT utilizes to improve immune-mediated tumor response is limited. Moreover, not all cancer types may benefit from ICB with or without RT, likely necessitating additional maneuvers to enhance the efficacy of these treatments for many tumor types. Accumulating data point toward a role for pattern recognition receptors (PRRs) that are normally responsible for sensing pathogen-associated molecular patterns to activate the innate immune system and optimize immune response. RT may similarly promote the engagement of PRR pathways, resulting in activation of dendritic cells (DCs) that facilitate T cell cross-priming. The types of PRRs, the role of PRRs expressed in tumor cells, the nature of the ligands that engage PRRs, and how such events might converge on DC function after RT are not well understood. Therefore, to complement parallel clinical trials that test the combination of RT + ?CTLA4 + ?PD1 in patients with advanced cancer, this project seeks to investigate how RT mediates immunomodulatory effects through PRRs and how these signaling events get relayed to DCs to enhance the T cell repertoire. In order to expand the types of cancers that may benefit from RT + ICB, this proposal also examines how engagement of CD40 can non- redundantly activating DCs to further improve response particularly for poorly immunogenic tumors. Thus, by understanding the immunomodulatory mechanism of action of RT, its limitations, and ways to break through therapeutic barriers, our goal is to broaden the efficacy of RT + ICB to more patients in next generation clinical trials.

Public Health Relevance

Radiation can improve response to immune checkpoint blockade (ICB) in pre-clinical models and is being tested in clinical trials. How radiation (RT) exerts immune stimulatory effects to enhance ICB is unclear. Understanding the mechanism of action of RT, its limitations, and ways to break through therapeutic barriers has the potential to expand the number of patients that benefit from combination therapy, while also providing biomarkers for patient selection. We address these goals by examining how RT activates tumor cell intrinsic anti-viral signaling pathways and how this impacts dendritic cells to diversify the repertoire of T cells that can be reactivated by ICB. We examine how this signaling pathway might be exploited as a potential biomarker for the immune stimulatory effects of RT and complement these efforts by investigating additional therapeutic pathways that non-redundantly enhance the efficacy of RT + ICB across multiple cancer types.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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University of Pennsylvania
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Patel, Shetal A; Minn, Andy J (2018) Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies. Immunity 48:417-433
Vonderheide, Robert H (2018) The Immune Revolution: A Case for Priming, Not Checkpoint. Cancer Cell 33:563-569
Liu, Shujing; Zhang, Gao; Guo, Jianping et al. (2018) Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis. Nat Commun 9:5426