Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.

Radiotherapy (RT) and chemotherapy can induce immune responses, but not much is known regarding treatment-induced immune changes in patients. This exploratory study aimed to identify potential prognostic and predictive immune-related proteins associated with progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). In this prospective study, patients with stage I NSCLC treated with stereotactic body radiation therapy (n = 26) and patients with stage III NSCLC treated with concurrent chemoradiotherapy (n = 18) were included. Blood samples were collected before (v1), during (v2), and after RT (v3). In patients with stage I NSCLC, CD244 (HR: 10.2, 95% CI: 1.8–57.4) was identified as a negative prognostic biomarker. In patients with stage III NSCLC, CR2 and IFNGR2 were identified as positive prognostic biomarkers (CR2, HR: 0.00, 95% CI: 0.00–0.12; IFNGR2, HR: 0.04, 95% CI: 0.00–0.46). In addition, analysis of the treatment-induced changes of circulating protein levels over time (Δv2/v3−v1) also identified CXCL10 and IL-10 as negative predictive biomarkers (CXCL10, HR: 3.86, 95% CI: 1.0–14.7; IL-10, HR: 16.92 (2.74–104.36)), although serum-induced interferon (IFN) response was a positive prognostic. In conclusion, we identified several circulating immunogenic proteins that are correlated with PFS in patients with stage I and stage III NSCLC before and during treatment.

Background: The majority of patients with pancreatic cancer develops cachexia. The mechanisms underlying cancer cachexia development and progression remain elusive, although tumour‐derived factors are considered to play a major role. Pancreatic tumour organoids are in vitro three‐dimensional organ‐like structures that retain many pathophysiological characteristics of the in vivo tumour. We aimed to establish a pancreatic tumour organoid biobank from well‐phenotyped cachectic and non‐cachectic patients to enable identification of tumour‐derived factors driving cancer cachexia.Methods: Organoids were generated from tumour tissue of eight pancreatic cancer patients. A comprehensive pre‐operative patient assessment of cachexia‐related parameters including nutritional status, physical performance, body composition, and inflammation was performed. Tumour‐related and cachexia‐related characteristics of the organoids were analysed using histological stainings, targeted sequencing, and real‐time–quantitative PCR. Cachexia‐related factors present in the circulation of the patients and in the tumour organoid secretome were analysed by enzyme‐linked immunosorbent assay.Results: The established human pancreatic tumour organoids presented typical features of malignancy corresponding to the primary tumour (i.e. nuclear enlargement, multiple nucleoli, mitosis, apoptosis, and mutated KRAS and/or TP53). These tumour organoids also expressed variable levels of many known cachexia‐related genes including interleukin‐6 (IL‐6), TNF‐α, IL‐8, IL‐1α, IL‐1β, Mcp‐1, GDF15, and LIF. mRNA expression of IL‐1α and IL‐1β was significantly reduced in organoids from cachectic vs. non‐cachectic patients (IL‐1α: −3.8‐fold, P = 0.009, and IL‐1β: −4.7‐fold, P = 0.004). LIF, IL‐8, and GDF15 mRNA expression levels were significantly higher in organoids from cachectic vs. non‐cachectic patients (LIF: 1.6‐fold, P = 0.003; IL‐8: 1.4‐fold, P = 0.01; GDF15: 2.3‐fold, P < 0.001). In line with the GDF15 and IL‐8 mRNA expression levels, tumour organoids from cachectic patients secreted more GDF15 and IL‐8 compared with organoids from non‐cachectic patients (5.4 vs. 1.5 ng/mL, P = 0.01, and 7.4 vs. 1.3 ng/mL, P = 0.07, respectively).Conclusions: This novel human pancreatic tumour organoid biobank provides a valuable tool to increase our understanding of the mechanisms driving cancer cachexia. Our preliminary characterization of the secretome of these organoids supports their application in functional studies including conditioned medium approaches and in vivo transplantation models.

This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined. Finally, clinical translation and reverse translation are discussed.