Priming versus propagating: distinct immune effects of an alpha- versus beta-particle emitting radiopharmaceutical when combined with immune checkpoint inhibition

Radiopharmaceutical therapy (RPT) enhances tumor response to immune checkpoint inhibitors (ICI) in preclinical models, but the effects of different radioisotopes have not been thoroughly compared. To evaluate mechanisms of response to RPT+ICI, we used NM600, an alkylphosphocholine selectively taken up by most tumors. Effects of ⁹⁰ Y-, ¹⁷⁷ Lu-, and ²²⁵ Ac-NM600 + ICIs were compared in syngeneic murine models, B78 melanoma (poorly immunogenic) and MC38 colorectal cancer (immunogenic). ⁹⁰ Y-/ ¹⁷⁷ Lu-/or ²²⁵ Ac-NM600 delivering 2 Gy mean tumor dose promoted tumor regression and improved survival when combined with ICIs in syngeneic mice bearing B78 or MC38 tumors. Regardless of the administered isotope, this combination was optimized with early ICI administration (days -3/0/3) relative to day 1 RPT. ⁹⁰ Y-NM600+ICI produced the greatest anti-tumor response for MC38, whereas high linear energy transfer (LET) alpha particle radiation from ²²⁵ Ac-NM600+ICI was most effective against poorly immunogenic B78 tumors. Flow cytometry and single cell RNA and T cell receptor (TCR) sequencing illuminated distinct mechanisms of ⁹⁰ Y- or ¹⁷⁷ Lu-NM600 in promoting expansion of existing adaptive immunity and of ²²⁵ Ac-NM600 in promoting immune priming when combined with ICI. Antitumor immune response can be achieved with appropriate application of α- or β- emitting RPT in combination with ICIs in diverse murine tumor models.