Extracellular matrix modulates T cell clearance of malignant cells in vitro
Claire Robertson1, Aimy Sebastian2, Aubree Hinckley2
1Materials Engineering Division, Engineering Directorate, LLNL,7000 East Ave, Livermore, CA, 94550, USA.
Abstract:
Despite the success of T cell checkpoint therapies, breast cancers rarely express these immunotherapy markers and are believed to be largely "immune cold" with limited inflammation and immune activation. The reason for this limited immune activation remains poorly understood. We sought to determine whether extracellular matrix substrate could contribute to this limited immune activation. Specifically, we asked whether extracellular matrix could alter T cell cytotoxicity against malignant mammary gland carcinoma cells (MCC) in a setup designed to promote maximal T cell efficacy (i.e., rich media with abundant IL2, high ratio of T cells to MCC). We observed that T cell clearance of MCC varied from 0% in collagen 4 or 6 conditions to almost 100% in fibronectin or vitronectin. Transcriptomics revealed that T cell function was defective in MCC/T cell cocultures on collagen 4 (Col4), potentially corresponding to greater expression of cytokines MCC cultured in this environment. In contrast, transcriptomics revealed an effective, exhausted phenotype on vitronectin. The observation that Col4 induces T cell suppression suggests that targeting tumor-ECM interactions may permit new approaches for utilizing immunotherapy in tumors which do not provoke a strong immune response.
Insights
Extracellular matrix components like collagen 4 suppress T cell activity against breast cancer cells. Targeting these tumor-extracellular matrix interactions may improve immunotherapy effectiveness in "immune cold" tumors.
Area of Science:
- Immunology
- Oncology
- Biomaterials Science
Background:
- Breast cancers are often "immune cold" with limited T cell activation, hindering immunotherapy success.
- The role of the extracellular matrix (ECM) in this immune suppression is not well understood.
Purpose of the Study:
- To investigate how ECM substrates influence T cell cytotoxicity against malignant mammary carcinoma cells (MCC).
- To identify specific ECM components that may contribute to the "immune cold" phenotype in breast cancer.
Main Methods:
- Co-culturing MCC with T cells on various ECM substrates (collagen 4, collagen 6, fibronectin, vitronectin).
- Assessing T cell-mediated MCC clearance rates.
- Performing transcriptomic analysis of T cells and MCC in co-culture.
Main Results:
- T cell clearance of MCC varied significantly by ECM substrate, from 0% on collagen 4/6 to nearly 100% on fibronectin/vitronectin.
- Collagen 4 (Col4) exposure led to defective T cell function and altered cytokine expression in MCC.
- Vitronectin exposure resulted in an effective, albeit exhausted, T cell phenotype.
Conclusions:
- Specific ECM components, particularly collagen 4, can actively suppress T cell function, contributing to immune evasion in breast cancer.
- Targeting tumor-ECM interactions presents a potential strategy to enhance immunotherapy efficacy in non-immunogenic breast tumors.
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