Joy, Joash D;
Malacrida, Beatrice;
Laforets, Florian;
Kotantaki, Panoraia;
Maniati, Eleni;
Manchanda, Ranjit;
Annibaldi, Alessandro;
... Balkwill, Frances R; + view all
(2024)
Human 3D ovarian cancer models reveal malignant cell intrinsic and extrinsic factors that influence CAR T cell activity.
Cancer Research
10.1158/0008-5472.CAN-23-3007.
(In press).
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Abstract
In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment (TME). Here, we describe the modulation of CAR T cell activity by malignant cells and fibroblasts in human 3D in vitro cell models of increasing complexity. In models combining mucin-1 (MUC1) and TnMUC1 CAR T cells with human high-grade serous ovarian cancer (HGSOC) cell spheroids, malignant cell-intrinsic resistance to CAR T cell killing was due to defective death receptor signaling involving TNFα. Adding primary human fibroblasts to spheroids unexpectedly increased the ability of CAR T cells to kill resistant malignant cells as CCL2 produced by fibroblasts activated CCR2/4+ CAR T cells. However, culturing malignant cells and fibroblasts in collagen gels engendered production of a dense extracellular matrix that impeded CAR T cell activity in a TGFβ-dependent manner. A vascularized microfluidic device was developed that allowed CAR T cells to flow through the vessels and penetrate the gels in a more physiological way, killing malignant cells in a TNFα-dependent manner. Complex 3D human cell models may provide an efficient way of screening multiple cytotoxic human immune cell constructs while also enabling evaluation of mechanisms of resistance involving cell-cell and cell-matrix interactions, thus accelerating preclinical research on cytotoxic immune cell therapies in solid tumors.
| Type: | Article |
|---|---|
| Title: | Human 3D ovarian cancer models reveal malignant cell intrinsic and extrinsic factors that influence CAR T cell activity |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1158/0008-5472.CAN-23-3007 |
| Publisher version: | http://dx.doi.org/10.1158/0008-5472.can-23-3007 |
| Language: | English |
| Additional information: | © The Authors 2024. This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10193721 |
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