Optimising radiotherapy techniques for radiation–immune synergy in colorectal cancer
(2026)
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- Colorectal cancer (CRC) is a major health burden. Most cases are microsatellite stable (MSS) and are poorly responsive to immunotherapy. Sensitising MSS CRC to immunotherapy is a major challenge, for which radiotherapy (RT) may be an option, given the local and systemic immunomodulatory effects demonstrated preclinically. Treatment goals differ by stage: in locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) enables excellent local and distant control, allowing development of non-operative management strategies for quality of life improvement through organ preservation. In metastatic MSS CRC, overall survival remains poor due to limited therapeutic options. This work aimed to characterise RT-induced immune mechanisms in humans and to exploit this knowledge to optimise RT-immunotherapy combinations. Dedicated workflows using modern RT techniques were developed for LARC RT and liver stereotactic ablative RT (SABR). In LARC, cone-beam CT (CBCT)-guided online-adaptive RT (oART) was assessed for primary tumour dose escalation. By reducing planning target volume (PTV) margins compared with non-adaptive RT, oART enabled escalation without increasing toxicity risk. As rectal boost is widely performed despite lacking recommendations, a systematic review of boost techniques was performed, revealing high heterogeneity. Meta-analysis identified RT parameters associated with pathological complete response. Then, a protocol was proposed, evaluating a new TNT strategy in which tumour-draining lymph node (TDLN) RT is delayed from primary tumour RT to preserve the efficacy of immunotherapy given concomitantly. This aims to improve clinical complete response and to expand non-operative management eligibility. This proposed protocol should primarily be regarded as a basis for discussion, highlighting the multiple biological, technical, and clinical parameters that must be carefully considered when envisaging a combined radiotherapy–immunotherapy–chemotherapy strategy, rather than as a definitive therapeutic recommendation. In metastatic CRC, CBCT-guided oART was explored to avoid invasive radiopaque marker implantation for liver SABR. While automatic propagation of target volumes on daily CBCT required larger PTV to compensate for propagation errors, daily adaptation improved target coverage and organ-at-risk sparing. Mechanically assisted non-invasive ventilation (MANIV) for breath-hold enhanced CBCT quality, reduced inter-operator image-guided RT variability, and improved autosegmentation accuracy. Finally, RT-induced immune effects were analysed by RT dose and site in MSS CRC patient. Pre- and post-RT blood comparison showed only an increase of a CD4+ T cell subset. In tumours, analysis revealed activation of immune pathways in irradiated lesions rather than major changes in infiltrating immune cell composition.
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Pierrard, J. (2026). Optimising radiotherapy techniques for radiation–immune synergy in colorectal cancer. https://hdl.handle.net/2078.5/270896