A PD-L1 and VEGFR2 dual targeted peptide and its combination with irradiation for cancer immunotherapy

Although the blockade of immune checkpoint PD-1/PD-L1 has achieved great success, the lack of tumor-infiltrating immune cells and PD-L1 expression in the tumor microenvironment results in a limited response in certain tumor types. Thus, rational and optimal combination strategies were urgently needed. The combination of PD-1/PD-L1 blockade and anti-angiogenic therapy has been reported to have great potential. Here, a chimeric peptide OGS was designed by conjugating the peptides OPBP-1 (8-12) and DA7R targeting PD-L1 and VEGFR2, respectively. OGS could bind to both human and mouse PD-L1 with high affinity and block the PD-1/PD-L1 interaction, and also inhibit the migration and tube formation of HUVEC cells in wound healing and tube formation assays. To further prolong the half-life of OGS, it was modified by coupling with peptide DSP which has a high binding affinity to both human serum albumin (HSA) and mouse serum albumin (MSA) to form the peptide DSPOGS. DSPOGS could not directly affect the viability, apoptosis, and cell cycle of tumor cells in vitro, while significantly inhibiting the tumor growth in the MC38 mouse model. DSPOGS could elicit a potent anti-tumor immune response and inhibit tumor angiogenesis, with the enhancement of tumor infiltrating CD8+ T cells and the IFN-γ secreting CD8+ T cells in the spleen and tumor-draining lymph node. Further, the combination of radiotherapy with DSPOGS could dramatically improve the therapeutic efficacy. Our study could provide a promising paradigm for the combination of immune checkpoint blockade, anti-angiogenesis, and radiotherapy.