Abstract IA003: Radiotherapy effects on tumor microenvironment
Authors: Formenti Silvia 
Published: March 2021

Abstract
Radiation therapy (RT) exerts multiple effects on the tumor and its microenvironment, affecting immunity, metabolism and the microbiome (Heather M. McGee et al. Clin Cancer Res 2019;25:2969-2974). Radiation has profound and sustained effects on non-malignant tissue, including epithelial to mesenchymal transition (EMT) and carcinogenesis. Seminal experiments from Barcellos-Hoff' s lab originally demonstrated the capacity of RT to induce EMT of non-malignant epithelial cells (Andarawewa, KL et al: Cancer Res 2007; 67: (18). September 15, 2007). Burma et al demonstrated in an in vivo model of gliomas engineered after loss of one allele of Trp53 and Pten, that mice were highly susceptible to radiation-induced gliomagenesis in a linear energy transfer (LET)-dependent manner, possibly dependent on the increasing degree of irreparable DNA breaks with increasing LET (Todorova PK et al Cancer Res 2007; 67: (18). September 15, 2007). Interestingly, the histopathology of RT-induced high grade gliomas in this model mimics that of human glioblastoma, with similar patterns of necrosis, pseudo-palisading and nuclear atypia. This effect has translational implications, in view of the fact that the adjacent irradiated brain after standard post-operative RT to GBM is the most common site of recurrence (Gupta K and Burns TC: Frontiers in Oncology, 2018). Radiation is a powerful inducer of immunogenic cell death (ICD) of cancer cells, by releasing of DAMPs such as high mobility group box protein 1 (HMGB1), ATP and translocation of calreticulin to cell surface. In response to DNA damage, cytosolic DNA released from the nucleus mitochondria activates sensors like cGAS/STING, leading to an increase in IFNβ, that recruits and activates BAFT3+ dendritic cells, crucial agents for cross-presentation and cross-priming of CD8+ T cells. Radiation also increases the trafficking of activated CD8+ T cells by releasing CXCL16, a chemokine that binds to CXCR6 (Matsumura et al., J Immunol 181:3099-3107 2008). Recent evidence has demonstrated how as part of DNA damage response to RT, tumor mutations are expressed and can generate neoantigens that contribute to sustained immune responses in patients (Nature Medicine, 2018; 24;12:1845). Consequently, RT can recruit both the innate and adaptive immune response and, in combination with immune checkpoint blockade (ICB) can convert the irradiated tumor into an in situ vaccine. The choice of technical parameters like radiation dose rate, dose and fractionation and the type of field chosen, all impact on the success of RT and immunotherapy combinations, as demonstrated by impairment of immune response when nodal regions are included in the field treated by RT and ICB (Marciscano A et al: Clin Cancer Res: 4(20) October 15, 2018). The widespread access to radiotherapy centers and the ease to include a standard modality like RT in clinical trials have have rendered it one of the tools of modern immunotherapy of cancer, by exploiting RT effects on tumor and TME, beyond its classical cytocidal potential.
Citation Format: Silvia Formenti. Radiotherapy effects on tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA003.