Yi YuanFollow

Author ORCID Identifier

0000-0003-1821-2178

Date of Award

12-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Zhiren Liu

Second Advisor

Jenny Yang

Third Advisor

Wei Zhou

Abstract

Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin αvβ3 at a novel site. ProAgio induces the apoptosis of cells that express high levels of the integrin. Activated cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in tumors express high levels of integrin αvβ3. ProAgio simultaneously and specifically induces apoptosis in CAFs and aECs in tumors. We provide evidence that depletion of CAFs and elimination of leaky tumor angiogenic vessels by ProAgio alter tumor immunity. ProAgio reduces CD4+ Treg and MDSC and increases CD8+ T-cells in the tumor. The enhancement of immune activity within the tumor is indicative of ProAgio’s ability to shift the immune balance in favor of tumor eradication. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreased the Programmed Death Ligand 1 (PD-L1) levels in the stroma areas surrounding the tumors, and thus strongly increased the delivery of anti-PD-L1 antibody to the target cancer cells. This improved delivery mechanism not only augments the effectiveness of immunotherapy but also suggests the potential for better therapeutic outcomes. The impact of ProAgio on tumor immunity provides strong synergistic treatment effects of checkpoint inhibitor immunotherapies for lung cancer treatment. Additionally, ProAgio enhances the efficacy of chemotherapeutics by depleting CAFs and angiogenic tumor vessels, thereby weakening the tumor’s defenses. This strategy modulates tumor immunity by simultaneously depleting CAFs and tumor angiogenic vessels using a rationally designed protein that induces apoptosis in integrin-expressing cells. The study offers a unique opportunity to enhance cancer immunotherapies, especially for patients with tumors of dense stroma and high angiogenesis.

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