Anticancer nanocage platforms for combined immunotherapy designed to harness immune checkpoints and deliver
In Seon Jeon1, Jae Do Yoo1, Smriti Gurung2
1Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; CMRI, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.
Abstract:
The interaction of programmed cell death 1 ligand 1 (PD-L1) with its receptor, programmed cell death 1 (PD-1), inhibits T cell responses. Monoclonal antibodies that block this interaction have been shown effective as immunotherapy. However, only a subset of cancers exhibits a durable response to PD-1/PD-L1 blockade. Moreover, antibody-based immune checkpoint blockade is costly and is occasionally accompanied by systemic side effects. To overcome these limitations of antibody-based immune checkpoint blockade, an immune checkpoint-blocking ferritin nanocage displaying 24 PD-L1 binding peptides (PD-L1pep1) on its surface was designed and constructed. These ferritin nanocages displaying PD-L1pep1 (PpNF) specifically bind to PD-L1 expressed on cancer cells or to purified PD-L1 with a ~30 nM binding affinity. The addition of PpNF to co-cultures of T cells and cancer cells inhibited PD-1/PD-L1 interactions and restored T cell activities. In a mouse model of syngeneic colon cancer, PpNF specifically targeted tumors and showed antitumor activity. Moreover, PpNF nanocages encapsulating the chemotherapeutic drug doxorubicin had more potent antitumor activity than a monoclonal antibody against PD-L1. These results demonstrate that ferritin nanocages displaying surface PD-L1pep1 can be efficiently applied for immunotherapy, especially when encapsulating small chemotherapeutic drugs. These nanocages may have promise as an immunotherapeutic nanomedicine against various solid tumors.
Insights
New ferritin nanocages block the PD-1/PD-L1 immune checkpoint, restoring T cell activity. These nanomedicines show promise for cancer immunotherapy, especially when combined with chemotherapy drugs.
Area of Science:
- Immunotherapy
- Nanomedicine
- Cancer Biology
Background:
- The PD-1/PD-L1 pathway is a key immune checkpoint that inhibits T cell responses.
- Current antibody-based therapies targeting PD-1/PD-L1 are effective but limited to a subset of cancers and can cause side effects.
- There is a need for alternative, more effective immunotherapeutic strategies.
Purpose of the Study:
- To develop a novel nanomedicine for immune checkpoint blockade.
- To evaluate the efficacy of ferritin nanocages displaying PD-L1 binding peptides (PpNF) in preclinical cancer models.
- To assess the potential of PpNF as a drug delivery system for chemotherapy.
Main Methods:
- Engineered ferritin nanocages displaying PD-L1 binding peptides (PpNF).
- In vitro assays to assess PD-1/PD-L1 interaction inhibition and T cell activity restoration.
- In vivo studies using a syngeneic colon cancer mouse model.
- Evaluation of PpNF loaded with doxorubicin for enhanced antitumor activity.
Main Results:
- PpNF specifically binds to PD-L1 with high affinity (~30 nM).
- PpNF effectively inhibits PD-1/PD-L1 interactions and restores T cell activity in vitro.
- PpNF demonstrates tumor targeting and significant antitumor activity in a colon cancer mouse model.
- PpNF-doxorubicin combination therapy showed superior antitumor efficacy compared to anti-PD-L1 monoclonal antibodies.
Conclusions:
- Ferritin nanocages displaying PD-L1 binding peptides offer a promising platform for cancer immunotherapy.
- PpNF can overcome limitations of current antibody-based immune checkpoint blockade.
- This nanomedicine approach holds potential for treating various solid tumors, particularly when combined with chemotherapeutics.
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