A PD-L1 and VEGFR2 dual targeted peptide and its combination with irradiation for cancer immunotherapy
Ling Jiao1, Qingyu Dong1, Wenjie Zhai1
1School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
Abstract:
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.
Insights
A novel peptide conjugate, D-SPOGS, combines immune checkpoint blockade and anti-angiogenic therapy to enhance anti-tumor immunity and inhibit tumor growth. Combining D-SPOGS with radiotherapy further improves therapeutic efficacy.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Immune checkpoint inhibitors like PD-1/PD-L1 blockade show success but have limited response in some tumors due to insufficient tumor-infiltrating immune cells and PD-L1 expression.
- Combination strategies are crucial for improving treatment efficacy, with PD-1/PD-L1 blockade and anti-angiogenic therapy showing significant potential.
Purpose of the Study:
- To design and evaluate a novel chimeric peptide conjugate, D-SPOGS, that targets both PD-L1 and VEGFR2, aiming to enhance anti-tumor immune responses and inhibit angiogenesis.
- To assess the therapeutic efficacy of D-SPOGS alone and in combination with radiotherapy in a preclinical tumor model.
Main Methods:
- A chimeric peptide OGS was constructed by conjugating OPBP-1 (targeting PD-L1) and D-A7R (targeting VEGFR2).
- OGS was modified with peptide D-SP to create D-SPOGS for prolonged half-life via serum albumin binding.
- In vitro assays assessed OGS's binding affinity and anti-angiogenic properties. In vivo studies evaluated D-SPOGS efficacy in the MC38 mouse model, including immune cell infiltration and combination therapy with radiotherapy.
Main Results:
- D-SPOGS effectively blocked PD-1/PD-L1 interaction and inhibited endothelial cell migration and tube formation.
- D-SPOGS significantly inhibited tumor growth in the MC38 mouse model without direct toxicity to tumor cells in vitro.
- D-SPOGS promoted anti-tumor immune responses, increasing CD8+ T cell infiltration and IFN-γ secretion, and synergized with radiotherapy for enhanced therapeutic effects.
Conclusions:
- The peptide conjugate D-SPOGS represents a promising strategy for combined immune checkpoint blockade and anti-angiogenesis.
- D-SPOGS demonstrates significant anti-tumor activity and enhances anti-tumor immunity, offering a potential new therapeutic paradigm.
- Combination therapy with D-SPOGS and radiotherapy significantly improves therapeutic efficacy, warranting further clinical investigation.
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