Immunomodulatory effects of alpha vs beta radiopharmaceutical therapy in murine prostate cancer.

Abstract

BACKGROUND: Radiation therapy can modulate the tumor microenvironment (TME), influencing antitumor immune responses. This study compared the immunomodulatory effects of alpha-emitting (Ac) and beta-emitting (Lu) radiopharmaceutical therapies (RPT) using NM600 in murine prostate cancer models. METHODS: We assessed immunological changes in TRAMP-C1 and Myc-CaP tumor models treated withAc-NM600 orLu-NM600. Flow cytometry was used to profile immune cell populations, activation markers, and checkpoint molecules, while multiplex assays analyzed cytokine and chemokine expression. RESULTS: In general,Ac-NM600 elicited stronger immunomodulatory effects thanLu-NM600, including cell line dependent increased CD8/Treg ratios, activation of effector and memory T cells, and depletion of suppressive Tregs and MDSCs. The treatment elevated Th1 cytokines, pro-inflammatory chemokines, and checkpoint molecules like PD-1 on CD8+ T cells and PD-L1 on MDSCs, creating a more "hot" TME. CONCLUSION: Alpha-emittingAc-NM600 demonstrated superior ability to enhance antitumor immunity compared to beta-emittingLu-NM600. These findings support the use ofAc-NM600 in combination with immunotherapies for advanced prostate cancer treatment.