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Microfluidic Co-Culture Models for Dissecting the Immune Response in in vitro Tumor Microenvironments
Published on: April 30, 2021
An in situ hydrogel-mediated chemo-immunometabolic cancer therapy
Bo Wang1, Jing Chen2,3, Julia S Caserto4
1Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA. bowang@cornell.edu.
Abstract:
Metabolic reprogramming of the tumor microenvironment (TME) and poor immunogenicity are two of the challenges that cancer immunotherapies have to overcome for improved clinical benefits. Among various immunosuppressive metabolites that keep anti-tumor immunity in check, the tryptophan catabolite kynurenine (Kyn) is an attractive target for blockade given its role in mediating immunosuppression through multiple pathways. Here, we present a local chemo-immunometabolic therapy through injection of a supramolecular hydrogel concurrently releasing doxorubicin that induces immunogenic tumor cell death and kynureninase that disrupts Kyn-mediated immunosuppressive pathways in TME. The combination synergically enhances tumor immunogenicity and unleashes anti-tumor immunity. In mouse models of triple negative breast cancer and melanoma, a single low dose peritumoral injection of the therapeutic hydrogel promotes TME transformation toward more immunostimulatory, which leads to enhanced tumor suppression and extended mouse survival. In addition, the systemic anti-tumor surveillance induced by the local treatment exhibits an abscopal effect and prevents tumor relapse post-resection. This versatile approach for local chemo-immunometabolic therapy may serve as a general strategy for enhancing anti-tumor immunity and boosting the efficacy of cancer immunotherapies.
Insights
This study introduces a novel chemo-immunometabolic therapy using a hydrogel to release doxorubicin and kynureninase. This approach enhances anti-tumor immunity and improves survival in mouse cancer models.
Area of Science:
- Oncology
- Immunology
- Biomedical Engineering
Background:
- Cancer immunotherapies face challenges from tumor microenvironment (TME) metabolic reprogramming and poor immunogenicity.
- The metabolite kynurenine (Kyn) suppresses anti-tumor immunity via multiple pathways, making it a key therapeutic target.
Purpose of the Study:
- To develop a local chemo-immunometabolic therapy to overcome TME-mediated immunosuppression.
- To enhance tumor immunogenicity and unleash anti-tumor immunity for improved cancer treatment.
Main Methods:
- A supramolecular hydrogel was engineered to co-deliver doxorubicin (chemotherapy) and kynureninase (enzyme therapy).
- The hydrogel was administered via a single peritumoral injection in mouse models of triple-negative breast cancer and melanoma.
Main Results:
- The combined therapy synergistically enhanced tumor immunogenicity and promoted a shift towards a more immunostimulatory TME.
- Significant tumor suppression and extended mouse survival were observed following treatment.
- The therapy induced systemic anti-tumor surveillance, demonstrating an abscopal effect and preventing tumor relapse after resection.
Conclusions:
- Local chemo-immunometabolic therapy with the hydrogel is a promising strategy for enhancing anti-tumor immunity.
- This approach can significantly boost the efficacy of cancer immunotherapies and offers a versatile platform for cancer treatment.
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