O40 Impact of TGFβ inhibition and radiotherapy in a heterotopic rectal cancer mouse model. (19th June 2022)

• Record Type: Journal Article
• Authors: Beach, Callum; Mul, Eoghan; Belnoue-Davis, Hayley; Valbuena, Gabriel; Molino, Monica Olcina del; Maughan, Tim; Leedham, Simon
• Is Part Of: Gut. Volume 71(2022)Supplement 1
• Page Start: A24
• Page End: A24
• Publication Date: 2022-06-19
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2022-BSG.40
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Introduction: Current management of rectal cancers (RC) includes radiotherapy as these low tumours have a fixed position within the pelvis. Response to radiotherapy can be highly variable, with data from the S:CORT consortium showing a negative association between tumour response to radiation and TGFβ activation status. The pleiotrophic morphogen TGF is implicated in fibroblast activation and immune cell evasion, with TGF inhibition enhancing radiosensitivity in a mouse lung cancer model (Lan et al., 2021). Here we have established a heterotopic in vivo model of RC to assess the impact of combining radiotherapy and a novel TGFβ inhibitor. Methods: Organoids were cultured from an autochthonous RC mouse model with APC -/-, KRAS G12D, p53 -/-, TGFβR1 -/- (AKPT) tumours. Organoids were implanted in C57BL/6 mice subcutaneously to establish tumours. These mice were then randomised into control, TGFβ inhibitor, radiation, and combination treatment groups. The TGFβ inhibitor was given prior to irradiation then on a five-day schedule. Tumours were harvested for RNAseq and multiplex imaging for assessment of treatment specific cell population and transcriptional changes. Results: TGFβ inhibition alone had no impact on tumour growth or mouse survival. Irradiation alone showed modest effect on survival with tumours temporarily arrested. Combination therapy proved significantly more effective, with prolonged tumour arrest. Additionally, multiplex analysis of tumours post-treatment demonstrated a change in the immune cell population and overall stromal structure. Notably, inhibition of TGFβ caused an increase in α-SMA + cancer-associated fibroblasts. Conclusions: Heterotopic injection of murine colorectal cancer organoids is a tractable and reproducible model for preclinical testing of combination radiotherapy, including novel agents. Irradiation of the AKPT organoid-derived tumours caused an initial arrest of tumour growth, which was enhanced by TGFβ inhibition. RNAseq and multiplex analysis demonstrated combined therapy impacted the remodelling of immune and stromal cell landscapes. This study implicates that TGFβ inhibition and irradiation combined may ameliorate the anti-tumour effect of radiation through maintaining immunogenicity and preventing the development of radioresistance. Reference: Lan Y, et al . Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer Cell 2021;39 (10):1388–1403.e1310.