Abstract 805: Macrophages protect salivary glands from ionizing radiation

Abstract Background: Radiation-induced xerostomia (RIX) is a common side-effect of radiation therapy in patients with head and neck cancer. Our group has previously demonstrated that MSC(M) injection into irradiated murine SMG tissue results in an improvement in salivary function and improvement in glandular health (% saliva in MSC v PBS groups). which corresponds to alterations in macrophages. Our clinical studies have demonstrated that MSC(M) injection into salivary glands is safe and effective. However, the full mechanism behind this effect remains unknown. We hypothesized that MSC(M)s in the SMG are affectingimpact tissue-resident macrophage activity and/or promotein macrophage traffickingg the influx of new macrophages to mediate improved salivary function. Here we test whether macrophages modulate the response to radiation in our mouse model of RIX and whether MSC(M)s can modulate salivary tissue resident macrophages. Methods: Clodronate liposomes delivered via tail vein injection were used to deplete macrophages in C57/BL6 mice prior to irradiation treatment (15 Gy) of SMGs with 15 Gy. Saliva production was monitoredmonitored, and glands were collected for histology at 3-, 7-, and 60-days post-irradiation. Primary, marrow-derived MSCs (MSC(M)) from C57/B6 male mice were isolated, cultured, and characterized using the immune monitoring 48-plex Luminex assay to characterize the secretion profile of immunomodulatory chemokines. Results: Macrophage depletion was confirmed via flow cytometry of mouse spleens. Clodronate-treated mice produced less saliva than control mice (92% vs 71% percent decrease respectively) consistent with a protective effect of macrophages. Secretome analysis of MSC(M) revealed a robust secretion profile with high levels of macrophage associated proteins including CCL2 (1527 pg/mL), CCL7 (332.18 pg/mL), CXCL1 (311.41 pg/mL), and CCL5 (157.62 pg/mL). These data suggest that MSC(M)s may have the capacity to modulate recruited and tissue-resident SMG macrophages. This is currently being tested. Conclusions: Our data suggests a beneficial role of macrophages in the natural response to radiation in the murine SMG. Previous data from our lab demonstrates a benefit from MSC injection after RT-exposure, and our secretome analysis of these cells show the immunomodulatory capacity of our MSC line. Future experiments must be done evaluating the effectiveness of MSC injection in our immune depleted models to determine whether MSCs are directly impacting the macrophages in the radiation damaged gland. Citation Format: Dimitri Scofield, Cristina Paz, Jasmine Robinson, Kwang Nickel, Randy Kimple. Macrophages protect salivary glands from ionizing radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 805.