WAN, ZHUOYA
(2022)
DESIGNING IMMUNOTHERAPIES FOR CANCER TREATMENT.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The immunosuppressive tumor microenvironment (TME) represents one of the hallmarks of cancer and underlies the basis for immune evasion and acquired immunotherapy-resistance for cancer therapy. Significant clinical success has been made in cancer treatment through blocking the T cell checkpoints, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and Programmed Death 1 (PD-1). However, only a subset of patients respond to such approaches.
The reason of non-response is very complicated. On the one hand, additional immunosuppressive mechanisms exist in the TME. A better understanding of the mechanism that regulates the immunosuppressive TME plays a crucial role for developing more efficacious immunotherapies and combination strategies. Here, we reported a novel role of the metabotropic glutamate receptor-4 (GRM4) in suppressing the anti-tumor immunity. We revealed in three murine syngeneic tumor models (B16, MC38, and 3LL) that either genetic knockout (Grm4−/−) or pharmacological inhibition led to significant delay in tumor growth and synergized with immune checkpoint inhibitors in male mice. Mechanistically, perturbation of GRM4 resulted in a strong anti-tumor immunity by promoting natural killer (NK), CD4+ and CD8+ T cells towards an activated, proliferative, and functional phenotype. Single-cell RNA-sequencing and T Cell Receptor (TCR) profiling further defined the clonal expansion and immune landscape changes in CD8+ T cells. Mechanistically, Grm4-/- intrinsically activated IFN-γ production in CD8+ T cells through a cAMP/CREB-mediated pathway. Our study appears to be of clinical significance as a signature of NKhigh-GRM4low and CD8high-GRM4low correlated with improved survival in melanoma patients. Therefore, targeting GRM4 could be exploited as a new approach for cancer immunotherapy.
Alternatively, the use of free drug raises the issue of water-solubility, rapid blood elimination and metabolism. Improvement in drug bioavailability and/or codelivery of multiple drugs via a nanocarrier represents a promising strategy to improve therapeutic outcome and patient compliance. We developed a dual-function immuno-stimulatory polymeric prodrug carrier modified with pendent indoximod, an indoleamine 2,3-dioxygenase (IDO) inhibitor that can be used to reverse immune suppression, for co-delivery of Doxorubicin (Dox), a hydrophobic anticancer agent that can promote immunogenic cell death (ICD) and elicit antitumor immunity. The resulting carrier denoted as POEG-b-PVBIND, consisting of poly (oligo (ethylene glycol) methacrylate) (POEG) hydrophilic blocks and indoximod conjugated hydrophobic blocks, is rationally designed to improve immunotherapy by synergistically modulating the tumor microenvironment (TME). Our data showed Dox/POEG-b-PVBIND micelles led to significantly improved tumor regression in an orthotopic murine breast cancer model compared to both Dox-loaded POEG-b-PVB micelles (a control inert carrier) and POEG-b-PVBIND micelles alone, confirming the combination effect of indoximod and Dox in improving the overall antitumor activity.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
14 January 2022 |
| Date Type: |
Publication |
| Defense Date: |
26 October 2021 |
| Approval Date: |
14 January 2022 |
| Submission Date: |
5 January 2022 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
184 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Cancer immunotherapy, mGluR4, Drug delivery, RNA seq, and IDO |
| Date Deposited: |
14 Jan 2022 13:33 |
| Last Modified: |
14 Jan 2022 13:33 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42159 |
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