Third Party Funds Group - Sub project
Acronym: GRK 2599 FAIR P10
Start date : 01.01.2021
End date : 30.07.2025
It has become generally accepted that local radiotherapy of tumors with ionizing radiation induces innate and adaptive immunity besides DNA damage to cancerous tissue (Frey et al., 2015, Finkel et al., 2016, Kotter et al., 2015). However, anti-tumor immune responses induced by radiotherapy alone are rarely observed, most likely because of concurrent immunosuppressive properties of ionizing radiation (Frey et al., 2017; Derer et al., 2016). T cells were identified to play an essential role in radiation-induced anti-tumor immune responses (Werthmöller et al., 2015; Derer et al., 2016). The priming of CD8+ T cells by dendritic cells (DCs) against solid tumors is controlled by many cell sur-face receptors that regulate and fine-tune the immune response, e.g., by the programmed death-ligand (PD-L) 1/PD-1 axis (Shevtsov et al., 2019*). Even though targeting such co-inhibitory mole-cules, which can be expressed by tumor cells or DCs, with antibodies showed promising results in several solid tumor entities, still, the majority of patients fail to respond appropriately (Seidel et al., 2018*). It is, therefore, necessary to explore other mechanisms that potentially suppress the radia-tion-induced immune response against tumors.
Tumor necrosis factor receptor superfamily member 14 (TNFRSF14) and its ligands have been demonstrated to be involved in the pathogenesis of many inflammatory diseases, but this network also seems to suppress anti-tumor immune responses (Derre et al., 2010*). The binding of TNFRSF14 to B and T lymphocyte attenuator (BTLA) or CD160 delivers co-inhibitory signals to T cells, while the binding of TNFRSF14 to LIGHT acts as a co-stimulatory factor. TNFRSF14 expres-sion was shown to be associated with aggressive tumor features in breast cancer, and BTLA activa-tion is discussed to be responsible for inhibition of the function of CD8+ cancer-specific T cells in melanoma (Derre et al., 2010*, Tsang et al., 2017*). We previously showed in B16F10 melanoma and CT26 colorectal cancer tumor models that CD8+ T cells infiltrate in a timely-restricted manner into solid tumors following local irradiation (Seitz et al., 2019, Frey et al., 2017). Preliminary data indicate that these T cells do express PD-1 as analyzed in the B16F10 melanoma (Seitz et al., 2019) and TSA breast cancer model (unpublished data). It is currently unknown how TNFRSF14 and its ligands are expressed on tumor cells and immune cells in the tumor after ionizing radiation. In vitro, we observed that the abundance of TNFRSF14 expression is increased on B16-F10 and TSA tumor cells following ionizing radiation.