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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Muscleblind-like proteins are novel modulators of the tumor-immune microenvironment
Austin M Gabel1,2,3,4, Edie I Crosse1,2, Andrea E Belleville1,2,4,5
1Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.
Abstract:
Exploiting the immune system to eradicate cancer cells is an area of intense clinical study. However, the mechanisms that shape the tumor-immune microenvironment are incompletely understood. Here, we identify Muscleblind-like (MBNL) proteins as novel modulators of the tumor-immune microenvironment across diverse cancers. We demonstrate that loss of tumor MBNL expression results in an attenuated response to interferon gamma and reduced tumor antigen presentation in melanoma, breast cancer, and colorectal cancer cells. Parallel experiments in a syngeneic mouse melanoma model revealed that MBNL loss reduces tumor cell killing by CD8 + T cells in vitro and facilitates tumor escape from cytotoxic CD8 + T cell infiltration in vivo. Finally, we extended these studies to 29 human cancer types to find that MBNL expression levels are strongly associated with gene expression signatures of T cell tumor infiltration. These insights suggest that MBNL proteins play important roles in shaping the immune landscape across diverse malignancies.
Insights
Muscleblind-like (MBNL) proteins modulate the tumor-immune microenvironment. Loss of MBNL impairs anti-tumor immunity and T cell infiltration across various cancers, suggesting MBNL as a therapeutic target.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The tumor-immune microenvironment significantly impacts cancer progression and treatment response.
- Understanding the molecular mechanisms that regulate the tumor-immune microenvironment is crucial for developing effective cancer immunotherapies.
Purpose of the Study:
- To identify novel regulators of the tumor-immune microenvironment.
- To investigate the role of Muscleblind-like (MBNL) proteins in cancer immunity across diverse malignancies.
Main Methods:
- Assessed MBNL protein expression in cancer cells and human tumor samples.
- Utilized in vitro assays to evaluate interferon gamma response and antigen presentation.
- Performed in vivo experiments in a syngeneic mouse melanoma model.
- Analyzed gene expression data for T cell infiltration signatures in 29 human cancer types.
Main Results:
- Loss of MBNL expression attenuated interferon gamma response and tumor antigen presentation in melanoma, breast, and colorectal cancer cells.
- MBNL loss reduced CD8+ T cell killing in vitro and promoted tumor escape from T cell infiltration in vivo.
- MBNL expression levels correlated with T cell infiltration signatures across 29 human cancer types.
Conclusions:
- Muscleblind-like (MBNL) proteins are novel modulators of the tumor-immune microenvironment.
- MBNL proteins play a significant role in shaping anti-tumor immunity and T cell infiltration.
- MBNL proteins represent potential therapeutic targets for enhancing cancer immunotherapy.
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