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<p>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- (<sup>225</sup>Ac) and β-emitting (<sup>90</sup>Y, <sup>177</sup>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 <sup>90</sup>Y-NM600 + ICI and in B78 and Myc-CaP to <sup>225</sup>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月26日

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

摘要

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- (225Ac) and β-emitting (90Y, 177Lu) 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 90Y-NM600 + ICI and in B78 and Myc-CaP to 225Ac-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.