The Effects of Clinically Relevant Radionuclides on the Activation of an IFN1 Response Correlate with Radionuclide Half-life and Linear Energy Transfer and Influence Radiopharmaceutical Antitumor Efficacy

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.