Journal Article

Priming versus propagating: distinct immune effects of alpha- versus beta-particle emitting radiopharmaceuticals when combined with immune checkpoint inhibition in mice

Bio Idrissou, Malick, Bednarz, Bryan P., Massey, Christopher F., Pinchuk, Anatoly N., Hernandez, Reinier, Ong, Irene M., Powers, Maria, Jin, Won Jong, Vera, Jessica M., Choi, Cynthia, Oñate, Alejandro J., Shea, Amanda G., Kerr, Caroline P., Liu, Peng, Weichert, Jamey P., Ferreira, Carolina A., Grudzinski, Joseph J., Adeniyi, Adedamola, Erbe, Amy K., Hyun, Meredith, Welch Schwartz, René, Comas Rojas, Hansel, Takashima, Maya, Clark, Paul A., Kwon, Ohyun, Morris, Zachary S.

2026

Overview

Radiopharmaceutical therapy (RPT) synergises with immune checkpoint inhibitors (ICI), but comparison of immunomodulation by different radioisotopes is lacking. Here, we evaluate mechanisms of response and timing of ICI administration relative to α- ( 225 Ac) and β-emitting ( 90 Y, 177 Lu) radioisotope therapy, coupled with alkylphosphocholine NM600, when combined with dual (anti-PD-L1 and anti-CTLA4) ICI, using syngeneic poorly immunogenic (B78 and Myc-CaP) and immunogenic (MC38) murine models. Regardless of the isotope, RPT delivering 2 Gy mean tumor dose promotes tumor regression and improves survival in B78 or MC38 tumor-bearing mice when combined with early ICI administration. Greatest anti-tumor responses are seen in MC38 to 90 Y-NM600 + ICI and in B78 and Myc-CaP to 225 Ac-NM600 + ICI. Flow cytometry and single-cell RNA and T cell receptor sequencing reveal that, combined with ICI, β-emitting radioisotopes expand existing adaptive immunity, whereas α-emitting radiopharmaceuticals initiate immune priming. Thus, appropriate application of α- or β-emitting RPT in combination with ICI achieves distinct antitumor immune responses. Preclinical studies indicate a synergistic effect of radiotherapy treatment (RT) and Immune checkpoint inhibitors (ICI) on tumor growth and metastasis. However, little is known about the immunomodulatory performance of different radioisotopes on the tumor microenvironment. Here, the authors employ alpha- versus beta-particle emitting radiopharmaceuticals in combination with dual ICI therapy and dissect mechanisms of in vivo immunomodulation and timing of ICI administration relative to RT, by comparing responses in immunogenic and non-immunogenic preclinical mouse models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/21 / 13/31 / 13/51 / 14/63 / 38/88 / 38/91 / 59/78 / 631/67/1059/485 / 631/67/580/1884/2323 / 64/60 / 692/308/2778 / Adaptive immunity / Alpha Particles - therapeutic use / Animal models / Animals / Antitumor activity / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - immunology / Beta Particles - therapeutic use / Beta rays / Biodistribution / Cell Line, Tumor / CTLA-4 protein / Dosimetry / Energy transfer / Female / Flow cytometry / Gene sequencing / Humanities and Social Sciences / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immune response / Immunogenicity / Immunomodulation / Immunotherapy / Inhibitors / Lymphocytes / Lymphocytes T / Melanoma / Metastases / Metastasis / Mice / Mice, Inbred C57BL / multidisciplinary / Myc protein / Patients / PD-L1 protein / Pharmaceuticals / Priming / Radiation therapy / Radiochemistry / Radioisotopes / Radiopharmaceuticals - pharmacology / Radiopharmaceuticals - therapeutic use / Science / Science (multidisciplinary) / Synergistic effect / T cell receptors / Toxicity / Tumor microenvironment / Tumors / Yttrium isotopes