Glioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the approximate Bayesian computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended fourier amplitude sensitivity test. Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored.
Checkpoint blockade immunotherapies harness the host's own immune system to fight cancer, but only work against tumors infiltrated by swarms of preexisting T cells. Unfortunately, most cancers to date are immune‐deserted. Here, a polymer‐assisted combination of immunogenic chemotherapy and PD‐L1 degradation is reported for efficacious treatment in originally nonimmunogenic cancer. “Priming” tumors with backbone‐degradable polymer‐epirubicin conjugates elicits immunogenic cell death and fosters tumor‐specific CD8+ T cell response. Sequential treatment with a multivalent polymer‐peptide antagonist to PD‐L1 overcomes adaptive PD‐L1 enrichment following chemotherapy, biases the recycling of PD‐L1 to lysosome degradation via surface receptor crosslinking, and produces prolonged elimination of PD‐L1 rather than the transient blocking afforded by standard anti‐PD‐L1 antibodies. Together, these findings establish the polymer‐facilitated tumor targeting of immunogenic drugs and surface crosslinking of PD‐L1 as a potential new therapeutic strategy to propagate long‐term antitumor immunity, which might broaden the application of immunotherapy to immunosuppressive cancers.
more » « less- PAR ID:
- 10457601
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Functional Materials
- Volume:
- 30
- Issue:
- 12
- ISSN:
- 1616-301X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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