Abstract SY36-01: Harnessing the radiation-induced local and systemic immune modulation to improve tumor control

Abstract Radiation Therapy (RT) is a highly effective anti-cancer treatment that is delivered to over half of all cancer patients. In the last century the major research focus was aimed at investigating how the direct cytotoxic effects of RT on cancer cells induced irreparable DNA damage and the determinants of intrinsic radiosensitivity. More recently the immunomodulatory effects of RT on both the immune effector cells within tumor microenvironment (TME) as well as within the surrounding normal tissue have been increasingly recognized. Despite recent technological advances in RT delivery with improved tumor targeting and minimizing exposure of surrounding healthy normal tissues, RT-induced normal tissue toxicity remains a major limitation to improving overall cancer outcomes and the quality of life of cancer survivors. An enhanced understanding of the RT induced immunological changes in the TME and surrounding irradiated normal tissue are therefore key to improving the therapeutic index of RT by enhancing tumor control and reducing normal tissue acute and late toxicity. The local effects of RT on the immune system within the irradiated TME can be either immunostimulatory or immunosuppressive. The RT induced immune changes within the TME appear to be heavily influenced by the immune effector cells infiltrations within the TME as well as by the RT dose and RT dose per fraction. The potential of RT in combination with immunoregulatory agents to drive systemic anti-tumor immune responses has been the subject of intense research in the laboratory and clinic over the last decade. Despite promising results in preclinical models with RT in combination with immune checkpoint inhibitors (ICI) and other immunoregulatory agents, clinical trial results have been largely disappointing with low overall tumor responses, presumably secondary to the dominant immunosuppressive TME and / or insufficient escalation of systemic anti-tumor responses. Despite the low overall tumor responses rates reported in some clinical trials, there have been some intriguing durable responses observed. In some of these clinical trials translational science has provided some insights into these durable responses, confirming the ability of RT to either generate novel neoantigens and /or to enhance anti-tumor immune responses in some cancer types. These clinical results underlie the importance of further investigation to increase our understanding of RT induced immunoregulatory effects as well as the requirement to move beyond ICI and develop novel immunoregulatory agents to potentially reprogram the TME aiming to further improve tumor responses. Opportunities to use immunoregulatory agents in combination with RT to potentially “reprogram” the TME and further improve local tumor control as well as generating systemic anti-tumor immune responses which will discussed in this presentation. RT-induced immunological responses in the normal tissue surrounding the tumor may also underly the acute and late-stage toxicity which may include multiple tissue components and immune mediators. These may include immune cells, the extracellular matrix, endothelial and epithelial cells and a myriad of chemokines and cytokines, including TGFβ, which is known to play a key role. In normal tissues exposed to RT during cancer therapy, acute immune changes may ultimately lead to chronic inflammation and RT-induced toxicity and organ dysfunction, which limits the quality of life of cancer survivors. In this presentation the focus will be on the acute increases in innate immune cells that are observed in the small and large intestine after RT, associated with significant increases in chemokines known to drive cell recruitment (chemokine ligands [CCL] 2, 3, 7, 11 and 17) and acute damage to crypt stem cells associated with RT induces shedding of cleaved glycocalyx components into the systemic circulation. Current work aimed at establishing the mechanisms and functional importance of these responses using cell depletion/KO mouse strategies, adopting strains with inflammatory chemokine receptor insufficiencies in vivo potential immune cross-talk between organs will be discussed. In conclusion, further research focused on understanding and potentially “harnessing” the RT induced immune response by therapeutically manipulating the RT induced immune response in both the TME and the surrounding normal tissue has great promise in further improving the both therapeutic index of RT and cancer outcomes Citation Format: Tim Illidge. Harnessing the radiation-induced local and systemic immune modulation to improve tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY36-01.