Jennifer Clare Jones MD, PhD, Presenter: Nothing to Disclose

Zhenyu Yao MD, PhD, Abstract Co-Author: Nothing to Disclose

Susan J. Knox MD, PhD, Abstract Co-Author: Nothing to Disclose

There is growing interest in combining immunotherapy (IT) with radiation therapy (RT). Successful combinations of external beam RT with IT will achieve local tumor control and induce anti-tumor immune responses against unirradiated sites of disease. The formation of immunological memory is regulated by stimulatory and inhibitory receptors on antigen presenting cells and T cells. Stimulatory receptors (CD28, TIM-1, ICOS, HVEM, CD40L, CD27, 4-1BB, OX40, CD30, and SLAM) are counterbalanced by four major coinhibitory receptors: CTLA4, TIM-4, BTLA, and PD-1. Biologic agents that modulate the activities of these receptors can promote anti-tumor immune responses. RT may be a useful adjunct to such IT, but our knowledge of the effects of RT on IT targets is limited. We examined costimulatory and coinhibitory receptor expression after radiation and identified receptors that are specifically upregulated after RT.

We quantified RT-induced changes in splenic immune cell populations with subset-specific cell surface monoclonal antibodies using flow cytometry. The cell subsets examined included conventional T cells, macrophages, and dendritic cells. C57/Bl6J mice were irradiated with single radiation doses (0, 2, 4, and 8 Gy), and splenocytes were analyzed 12, 24, 48, and 96 hours after RT.

RT selectively induces the expression of certain receptors, such as TIM-1, CD40, 4-1BB, PD-1, and PD-L1. Levels of PD-1 and its ligand, PD-L1, increase in a dose dependent manner after RT, and this enhancement persists for at least four days. The identification of PD-1 and PD-L1 as RT-induced coinhibitory receptors is novel and of particular therapeutic interest.

RT induces clear and predictable changes in the expression of certain costimulatory and coinhibitory receptors. Our results quantify the effects of RT on the cells and receptors that orchestrate immune responses.  Based on these results we hypothesize that combining PD-1 blockade with RT is a promising new RT + IT strategy. Further testing of this RT-IT combination in preclinical mouse models is warranted.

Our results establish a framework that will guide the development and optimization of RT + IT patient treatment strategies.

Jones, J, Yao, Z, Knox, S, Effects of Radiation on Immune Costimulatory Receptors.  Radiological Society of North America 2008 Scientific Assembly and Annual Meeting, February 18 - February 20, 2008 ,Chicago IL. http://archive.rsna.org/2008/6020727.html