Kerr Caroline P, Sheehan-Klenk Julia, Grudzinski Joseph J, Adam David P, Nguyen Thanh Phuong T, Ferreira Carolina A, Bates Amber M, Jin Won Jong, Kwon Ohyun, Olson Aeli P, Lin Wilson, Hyun Meredith, Jagodinsky Justin C, Powers Maria, Sriramaneni Raghava N, Clark Paul A, Shea Amanda G, Comas Rojas Hansel, Choi Cynthia, Massey Christopher F, Zangl Luke M, Pinchuk Anatoly N, Aluicio-Sarduy Eduardo, Kim KyungMann, Engle Jonathan W, Hernandez Reinier, Bednarz Bryan P, Weichert Jamey P, Morris Zachary S
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Cancer Immunol Res. 2025 Aug 1;13(8):1190-1206. doi: 10.1158/2326-6066.CIR-24-1191.
Radiopharmaceutical therapies (RPT) activate an IFN1 response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by 90Y, 177Lu, and 225Ac in vitro as unbound radionuclides and in vivo when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by using qPCR and flow cytometry. Therapeutic response to 225Ac-NM600 + anti-CTLA4 + anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of IFN genes (STING) knockout B78. The timing and magnitude of the IFN1 response correlated with radionuclide half-life and linear energy transfer. The ratio of CD8+ T cells to regulatory T cells increased in tumors 7 days after 90Y- and 177Lu-NM600 and on day 21 after 225Ac-NM600. 225Ac-NM600 + ICI improved survival in mice with wild-type but not STING knockout tumors when compared with monotherapies. Thus, we have found that the immunomodulatory effects of RPT vary with radioisotope and promote tumor cell STING-dependent enhanced response to ICIs in murine models. These findings have implications for the optimization of RPT-immunotherapy combinations and could guide the relative timing of therapies, the selection of isotope, and patient selection through tumor biomarkers.
放射性药物疗法（RPT）可激活肿瘤细胞中的IFN1反应。我们假设这种反应的时间和幅度因同位素而异。我们比较了90Y、177Lu和225Ac以未结合放射性核素形式在体外以及与肿瘤选择性烷基磷胆碱NM600螯合后在体内递送的等量剂量。通过qPCR和流式细胞术评估小鼠MOC2头颈癌和B78黑色素瘤中的反应。在野生型和干扰素基因刺激物（STING）敲除的B78中评估了对225Ac-NM600 +抗CTLA4 +抗PD-L1免疫检查点抑制（ICI）的治疗反应。IFN1反应的时间和强度与放射性核素半衰期和线性能量传递相关。90Y-NM600和177Lu-NM600注射后7天以及225Ac-NM600注射后21天，肿瘤中CD8 + T细胞与调节性T细胞的比例增加。与单一疗法相比，225Ac-NM600 + ICI可提高野生型肿瘤小鼠的生存率，但对STING敲除肿瘤小鼠无效。因此，我们发现RPT的免疫调节作用随放射性同位素而变化，并在小鼠模型中促进肿瘤细胞对ICI的STING依赖性增强反应。这些发现对优化RPT-免疫疗法组合具有启示意义，并可指导治疗的相对时间、同位素选择以及通过肿瘤生物标志物进行患者选择。
