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

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.