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

BACKGROUND

Radiation therapy can modulate the tumor microenvironment (TME), influencing antitumor immune responses. This study compared the immunomodulatory effects of alpha-emitting (225Ac) and beta-emitting (177Lu) radiopharmaceutical therapies (RPT) using NM600 in murine prostate cancer models.

METHODS

We assessed immunological changes in TRAMP-C1 and Myc-CaP tumor models treated with 225Ac-NM600 or 177Lu-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, 225Ac-NM600 elicited stronger immunomodulatory effects than 177Lu-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-emitting 225Ac-NM600 demonstrated superior ability to enhance antitumor immunity compared to beta-emitting 177Lu-NM600. These findings support the use of 225Ac-NM600 in combination with immunotherapies for advanced prostate cancer treatment.