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Improving cancer immunotherapy via co-delivering checkpoint blockade and thrombospondin-1 downregulator
Qingqing Xiao1, Xiaotong Li1, Chang Liu1
1School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Abstract:
The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy, despite considerable success in anti-tumor immunotherapy. The poor response of cancer cells to immune destruction is an essential contributor to the failure of checkpoint therapy. We hypothesized that combining checkpoint therapy with natural-product chemosensitizer could enhance immune response. Herein, a targeted diterpenoid derivative was integrated with the checkpoint blockade (anti-CTLA-4) to improve immunotherapy using thermosensitive liposomes as carriers. In vivo, the liposomes enabled the co-delivery of the two drug payloads into the tumor. Consequently, the regulatory T cell proliferation was restrained, the cytotoxic T cell infiltration was enhanced, and the profound immunotherapeutic effect was achieved. In addition, the immunotherapeutic effect of another clinically used checkpoint antibody, anti-PD-1, also benefited from the diterpenoid derivative. Of note, our mechanism study revealed that the targeted diterpenoid derivative increased the sensitivity of cancer cells to immune attack via THBS1 downregulation and the resultant destruction of THBS1-CD47 interaction. Collectively, co-delivering THBS1 inhibitor and checkpoint blockade is promising to boost cancer immunotherapy. We first time discovered that THBS1 suppression could strengthen checkpoint therapy.
Insights
Combining a natural compound with checkpoint blockade therapy enhances anti-tumor immunity by making cancer cells more susceptible to immune attack. This approach shows promise for improving cancer immunotherapy outcomes.
Area of Science:
- Immunology
- Oncology
- Drug Delivery
Background:
- Checkpoint blockade therapy shows promise in cancer immunotherapy but faces limitations due to modest efficacy in several malignancies.
- Poor response of cancer cells to immune destruction is a key factor limiting the success of checkpoint therapy.
- Combining checkpoint inhibitors with natural-product chemosensitizers may enhance anti-tumor immune responses.
Purpose of the Study:
- To investigate the potential of combining a targeted diterpenoid derivative with checkpoint blockade therapy to improve cancer immunotherapy.
- To evaluate the efficacy of co-delivering these agents using thermosensitive liposomes for targeted tumor delivery.
- To elucidate the underlying mechanisms by which the diterpenoid derivative enhances cancer cell sensitivity to immune attack.
Main Methods:
- Development and utilization of thermosensitive liposomes for co-delivery of a diterpenoid derivative and anti-CTLA-4 antibody.
- In vivo evaluation of the combined therapy's impact on regulatory T cell proliferation and cytotoxic T cell infiltration in tumors.
- Mechanism studies to determine how the diterpenoid derivative affects cancer cell sensitivity to immune attack, focusing on THBS1 and CD47 interactions.
Main Results:
- Liposomes successfully co-delivered the diterpenoid derivative and anti-CTLA-4 into the tumor site in vivo.
- The combination therapy significantly restrained regulatory T cell proliferation and enhanced cytotoxic T cell infiltration.
- The diterpenoid derivative was found to increase cancer cell sensitivity to immune attack by downregulating THBS1, disrupting the THBS1-CD47 interaction.
- The benefits of the diterpenoid derivative were also observed with another checkpoint antibody, anti-PD-1.
Conclusions:
- Co-delivery of a THBS1 inhibitor (diterpenoid derivative) and checkpoint blockade therapy is a promising strategy to enhance cancer immunotherapy.
- Suppression of THBS1 is a novel mechanism that can strengthen the efficacy of checkpoint therapy.
- This combined approach offers a potential new avenue for treating malignancies refractory to current immunotherapies.
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