Radiation induced lymphopenia (RIL) is a common and yet often ignored side effect of radiation therapy that has been observed for over 100 years. Numerous studies have demonstrated the correlation between RIL and inferior overall survival outcomes in nearly all cancer types that are treated with radiation therapy. To assess the causative link between RIL and poor disease outcomes, as well as its impact on therapy response, we have developed a mouse model of RIL. Using cone beam CT based image-guided radiation targeting the mid-thorax, we showed that conventionally fractionated radiation of 2 Gy x 5 fractions caused severe and sustained lymphopenia in both C57BL/6 (Th1) and BALB/c (Th2). Increasing the radiation dose and radiation field resulted in more pronounced RIL. Enlarging the volume to include the spleen along with the thorax resulted in greater than 90% elimination of circulating lymphocytes (CD8/CD4/CD19/NK cells). However, radiation to the head resulted in only minimal lymphodepletion suggesting site specific susceptibility to the development of severe RIL. The severity of the lymphodepletion was also unperturbed by rate of blood flow as the administration of varying anesthetics that caused 5 fold differences in heart rate did not alter the severity of RIL. Functionally, RIL abrogated the immunotherapeutic effectiveness of anti-CTLA4 mAb as lymphopenic mice bearing CT26 tumors had complete lack of response to anti-CTLA4 treatment as compared to its control littermates. Similarly, animals treated with radiotherapy had nearly complete amelioration of radiotherapy effectiveness in the setting of severe RIL. However, exogenous administration of IL-15 super agonist (IL-15 SA) (IL-15 and IL-15Rα-Fc) therapy replenished cytotoxic CD8+ T killer cells and natural killer cells to control levels which restored the tumoricidal effect of radiation therapy. Taken together our study have generated the evidence for the causative link between RIL and poorer disease outcomes and presented a potential therapeutic strategy to overcome the adverse effect of RIL.

Citation Format: Amrish Sharma, Shinya Neri, Bhanu P. Venkatesulu, Steven H. Lin. Preclinical model of radiation induced lymphopenia to identify abrogation strategies to enhance cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 473.