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T cell-responsive macroporous hydrogels for in situ T cell expansion and enhanced antitumor efficacy.

ABSTRACT: Adoptive T cell therapy has demonstrated great promise for treating cancer and other diseases. While extensive effort has been made to improve ex vivo expansion of T cells, strategies for maintaining the proliferation and function of T cells post adoptive transfer are still lacking. Here we report an injectable T cell-responsive macroporous hydrogel that enables in situ activation and expansion of T cells. The macroporous gel is composed of a polymeric network with dispersed macropores (∼150 μm) that are large enough to home T cells. In the presence of T cells that can gradually disrupt the gel network surrounding the macropores, activation cues can be gradually released for in situ activation and expansion of T cells. This T cell-responsive macroporous gel enables expansion of effector T cells in vivo, is stable over weeks upon subcutaneous injection, and results in enhanced CD8⁺ T cell response and antitumor efficacy. We further show that the T cell-responsive macroporous gel could achieve comparable antitumor efficacy to conventional T cell therapy with a much lower cell dose. This injectable, T cell-responsive macroporous gel provides a platform for in vivo expansion of engineered T cells in a controlled manner, for timely and effective treatment of diseases.

SUBMITTER: Bhatta R

PROVIDER: S-EPMC9868092 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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T cell-responsive macroporous hydrogels for in situ T cell expansion and enhanced antitumor efficacy.

Bhatta Rimsha R Han Joonsu J Liu Yusheng Y Bo Yang Y Wang Hua H

Biomaterials 20221216

Adoptive T cell therapy has demonstrated great promise for treating cancer and other diseases. While extensive effort has been made to improve ex vivo expansion of T cells, strategies for maintaining the proliferation and function of T cells post adoptive transfer are still lacking. Here we report an injectable T cell-responsive macroporous hydrogel that enables in situ activation and expansion of T cells. The macroporous gel is composed of a polymeric network with dispersed macropores (∼150 μm) ...[more]

PMID: 36566554

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Project description:IntroductionBiomaterials that enable in situ recruitment and modulation of immune cells have demonstrated tremendous promise for developing potent cancer immunotherapy such as therapeutic cancer vaccine. One challenge related to biomaterial scaffold-based cancer vaccines is the development of macroporous materials that are biocompatible and stable, enable controlled release of chemokines to actively recruit a large number of dendritic cells (DCs), contain macropores that are large enough to home the recruited DCs, and support the survival and proliferation of DCs.MethodsBio-adhesive macroporous gelatin hydrogels were synthesized and characterized for mechanical properties, porous structure, and adhesion towards tissues. The recruitment of immune cells including DCs to chemokine-loaded bioadhesive macroporous gels was analyzed. The ability of gels loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor extracellular vesicles (EVs) to elicit tumor-specific CD8+ T cell responses was also analyzed.ResultsHere we develop a bioadhesive macroporous hydrogel that can strongly adhere to tissues, contain macropores that are large enough to home immune cells, are mechanically tough, and enable controlled release of chemokines to recruit and modulate immune cells in situ. The macroporous hydrogel is composed of a double crosslinked network of gelatin and polyacrylic acid, and the macropores are introduced via cryo-polymerization. By incorporating GM-CSF and tumor EVs into the macroporous hydrogel, a high number of DCs can be recruited in situ to process and present EV-encased antigens. These tumor antigen-presenting DCs can then traffic to lymphatic tissues to prime antigen-specific CD8+ T cells.ConclusionThis bioadhesive macroporous hydrogel system provides a new platform for in situ recruitment and modulation of DCs and the development of enhanced immunotherapies including tumor EV vaccines. We also envision the promise of this material system for drug delivery, tissue regeneration, long-term immunosuppression, and many other applications.Supplementary informationThe online version contains supplementary material available at 10.1007/s12195-023-00770-2.

Dataset Information

T cell-responsive macroporous hydrogels for in situ T cell expansion and enhanced antitumor efficacy.

Publications

T cell-responsive macroporous hydrogels for in situ T cell expansion and enhanced antitumor efficacy.

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