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CD4+ T Cells Sensitize Quasimesenchymal Breast Tumors Lacking CD73 to Anti-CTLA4 Immune Checkpoint Blockade Therapy
Shiney Chandraganti1, Caitlyn Sams1, Sarthak Sahoo2
1Department of Biomedical and Translational Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York.
Abstract:
Although immune checkpoint blockade (ICB) therapy has generated dramatic responses in certain cancer types, breast tumors are largely unresponsive. Epithelial-mesenchymal plasticity (EMP) leads to the assembly of an immunosuppressive tumor microenvironment and drives resistance of breast tumors to immunotherapies. Importantly, targeting CD73 completely sensitizes quasi-mesenchymal (qM) breast tumors to anti-CTLA4 ICB therapy. However, the mechanism(s) of sensitization remained unknown. We demonstrate that targeting CD73 in qM breast tumors sensitizes them to anti-CTLA4 ICB therapy in a CD4+ T cell-dependent manner. Moreover, EMP results in elevated expression of cancer cell-intrinsic CD73 in human triple-negative breast cancers. Given the ability of qM cancer cells to metastasize and resist multiple therapies, these findings can instruct the formation of 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.
Significance:
EMP enables metastasis and drives resistance to multiple treatment regimens. Our work underscores the possibility of utilizing CD4+ T cells, CD73, and cancer plasticity as predictive criteria for responsiveness to immunotherapy.
Insights
Targeting CD73 sensitizes breast tumors to immunotherapy by engaging CD4+ T-cells. This approach may improve treatment for triple-negative breast cancers by overcoming resistance associated with epithelial-mesenchymal plasticity.
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 specific breast tumor subtypes to immunotherapy, but the underlying mechanisms are unclear.
Purpose of the Study:
- To elucidate the mechanism by which targeting CD73 sensitizes quasi-mesenchymal breast tumors to anti-CTLA4 immune checkpoint blockade therapy.
- To investigate the role of CD4+ T-cells in CD73-mediated sensitization.
- To explore the clinical relevance of CD73 expression in human triple-negative breast cancers.
Main Methods:
- Utilized a mouse model of quasi-mesenchymal breast tumors.
- Administered anti-CTLA4 immune checkpoint blockade therapy combined with CD73 targeting.
- Performed flow cytometry and immunohistochemistry to analyze immune cell populations and CD73 expression.
- Examined human triple-negative breast cancer samples.
Main Results:
- Targeting CD73 sensitized quasi-mesenchymal breast tumors to anti-CTLA4 therapy.
- Sensitization was dependent on the presence and function of CD4+ T-cells.
- Epithelial-mesenchymal plasticity correlated with increased cancer cell-intrinsic CD73 expression in human triple-negative breast cancers.
Conclusions:
- CD73 targeting enhances anti-CTLA4 immunotherapy efficacy in breast cancer through a CD4+ T-cell dependent mechanism.
- Elevated CD73 expression in quasi-mesenchymal breast cancer cells, particularly in triple-negative subtypes, presents a therapeutic target.
- CD73, CD4+ T-cells, and cancer cell plasticity may serve as predictive biomarkers for immunotherapy response in breast cancer.
