Nuclear imaging of PD-L1 expression promotes the synergistic antitumor efficacy of targeted radionuclide therapy and immune checkpoint blockade.

Abstract

In order to maximize synergistic effect of targeted radionuclide therapy (TRT) and immune checkpoint blockade (ICB) as well as reduce the toxicity, we pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy. As a novel targeted radiotherapeutic agent, ¹⁷⁷Lu-AB-3PRGD₂ targeting integrin α_vβ₃ was developed to achieve sustained antitumor effect by introducing an albumin binder (AB) into the structure of 3PRGD₂. The ¹⁷⁷Lu-AB-3PRGD₂ TRT as well as different types of combination therapies of ¹⁷⁷Lu-AB-3PRGD₂ TRT and anti-PD-L1 ICB were performed in animal models. The changes of PD-L1 expression in tumors after TRT were evaluated in vitro and in vivo by PD-L1-specific SPECT/CT imaging of ^99mTc-MY1523. ¹⁷⁷Lu-AB-3PRGD₂ showed improved tumor uptake and prolonged tumor retention, leading to significantly enhanced tumor growth suppression. Moreover, ¹⁷⁷Lu-AB-3PRGD₂ TRT remodeled the tumor immune microenvironment by upregulating PD-L1 expression and increasing tumor-infiltrating CD8⁺ T cells, facilitating immunotherapy. We found that the anti-PD-L1 treatment was more effective during the upregulation of tumor PD-L1 expression, and the time window could be determined by ^99mTc-MY1523 SPECT/CT. We developed a novel and long-acting radiotherapeutic agent ¹⁷⁷Lu-AB-3PRGD₂, and pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy, optimizing the therapeutic efficacy and reducing the cost and potential toxicity risks. This strategy could also be adapted for clinical practice, combining conventional radiotherapy or chemotherapy with ICB to enhance therapeutic efficacy.