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Published on: June 12, 2021
CD4+ T-cells sensitize quasi-mesenchymal breast tumors lacking CD73 to anti-CTLA4 immune checkpoint blockade therapy
Shiney Chandraganti1, Caitlyn Sams1, Sarthak Sahoo2
1Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Abstract:
Although immune checkpoint blockade therapy has generated dramatic responses in certain cancer types, breast tumors are largely unresponsive. Epithelial-mesenchymal plasticity leads to the assembly of an immunosuppressive tumor microenvironment and drives resistance of breast tumors to immunotherapies. Importantly, targeting CD73 completely sensitizes quasi-mesenchymal breast tumors to anti-CTLA4 immune checkpoint blockade therapy. However, the mechanism(s) of sensitization remained unknown. We demonstrate that targeting CD73 in quasi-mesenchymal breast tumors sensitizes them to anti-CTLA4 immune checkpoint blockade therapy in a CD4+ T-cell dependent manner. Moreover, epithelial-mesenchymal plasticity results in elevated expression of cancer cell-intrinsic CD73 in human triple negative breast cancers. Given the ability of quasi-mesenchymal cancer cells to metastasize and resist multiple therapies, these findings can instruct the formation of novel translational strategies for the treatment of human breast cancers. These findings also bring to the forefront the attractive possibility of utilizing the phenotypic plasticity of cancer cells along with CD73 and CD4+ T-cells as a predictive criterion for immunotherapy responsiveness.
Insights
Targeting CD73 enhances immunotherapy for mesenchymal-like breast tumors. This approach sensitizes tumors by engaging CD4+ T-cells, offering new treatment strategies for triple-negative breast cancer.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Breast tumors often resist immune checkpoint blockade therapy due to an immunosuppressive tumor microenvironment driven by epithelial-mesenchymal plasticity.
- CD73 targeting has shown potential in sensitizing resistant breast tumors, but the underlying mechanisms require elucidation.
Purpose of the Study:
- To investigate the mechanism by which targeting CD73 sensitizes quasi-mesenchymal breast tumors to anti-CTLA4 immune checkpoint blockade therapy.
- To explore the role of CD4+ T-cells in CD73-mediated sensitization.
- To examine the expression of CD73 in human triple-negative breast cancers.
Main Methods:
- Utilized a preclinical model of quasi-mesenchymal breast tumors.
- Administered anti-CTLA4 therapy in combination with CD73 targeting.
- Assessed tumor response and characterized the tumor microenvironment, focusing on CD4+ T-cell infiltration and function.
- Analyzed CD73 expression in human triple-negative breast cancer samples.
Main Results:
- Targeting CD73 sensitized quasi-mesenchymal breast tumors to anti-CTLA4 therapy.
- This sensitization was dependent on the presence and function of CD4+ T-cells.
- Epithelial-mesenchymal plasticity correlated with elevated cancer cell-intrinsic CD73 expression in human triple-negative breast cancers.
Conclusions:
- CD73 targeting enhances anti-CTLA4 immunotherapy efficacy in mesenchymal-like breast tumors through a CD4+ T-cell dependent mechanism.
- Elevated CD73 expression in mesenchymal-like cancer cells contributes to immunotherapy resistance.
- These findings support CD73 and CD4+ T-cells as potential biomarkers for predicting immunotherapy response in breast cancer.
