A multilayered blood vessel/tumor tissue chip to investigate T cell infiltration into solid tumor tissues
| Autor: | Dowon Moon, Seong-Eun Kim, Jaehyun Lee, Junsang Doh |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Vascular Endothelial Growth Factor A
T-Lymphocytes T cell Biomedical Engineering Bioengineering Immunotherapy Adoptive Biochemistry 03 medical and health sciences 0302 clinical medicine Neoplasms Tumor Microenvironment medicine Humans T cell extravasation 030304 developmental biology 0303 health sciences Tumor microenvironment Chemistry fungi T cell chemotaxis General Chemistry medicine.disease Chimeric antigen receptor Extravasation Endothelial stem cell medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Infiltration (medical) |
| Zdroj: | Lab on a Chip. 21:2142-2152 |
| ISSN: | 1473-0189 1473-0197 |
| DOI: | 10.1039/d1lc00182e |
| Popis: | Cancer immunotherapies based on the ability of T cells to recognize and kill tumor cells (TCs), including immune checkpoint blockade (ICB) therapy and chimeric antigen receptor (CAR) T cell therapy, have been greatly successful recently, but they are applicable for only a fraction of patients. One of the main challenges in cancer immunotherapy is the improvement of T cell infiltration into solid tumor tissues, as T cells can exert cytotoxicity against TCs only when they are in contact with TCs. T cells in the bloodstream infiltrate into solid tumor tissues by following two steps known as extravasation and interstitial migration. Herein, we developed a multilayered blood vessel/tumor tissue chip (MBTC) that allows systematic investigation on T cell tumor infiltration. The MBTC is composed of a top fluidic chamber, a porous membrane covered with an endothelial cell (EC) monolayer, and a collagen gel block encapsulating TCs. The full sequence of T cell tumor infiltration, including extravasation and interstitial migration, required for TC killing is demonstrated in the MBTCs: T cells applied through the top fluidic chamber of the MBTCs exhibited dynamic interactions with ECs for extravasation, including intraluminal crawling and transendothelial migration (TEM). After extravasation, T cells migrate toward TCs located at the bottom of a collagen block to kill them. Key characteristics of T cell dynamics in tumor microenvironments are recapitulated in the MBTCs: the vascular endothelial growth factor (VEGF) produced by TCs suppressed EC activation by inflammatory cytokines, or induced EC anergy, thereby significantly reducing T cell extravasation, whereas chemokines produced by TCs triggered T cell chemotaxis toward TCs. Anti-VEGF treatment in the MBTCs reverts EC anergy and promotes T cell infiltration, similar to the clinical effects of anti-VEGF. The MBTC is a useful model for pre-clinical evaluation of immunotherapeutics and the fundamental study of tumor immunology. |
| Databáze: | OpenAIRE |
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