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IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer
Nicholas R Hum1,2, Aimy Sebastian1, Kelly A Martin1
1Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA, United States.
Abstract:
Due to lack of targetable receptors and intertumoral heterogeneity, triple negative breast cancer (TNBC) remains particularly difficult to treat. Doxorubicin (DOX) is typically used as nonselective neoadjuvant chemotherapy, but the diversity of treatment efficacy remains unclear. Comparable to variability in clinical response, an experimental model of TNBC using a 4T1 syngeneic mouse model was found to elicit a differential response to a seven-day treatment regimen of DOX. Single-cell RNA sequencing identified an increase in T cells in tumors that responded to DOX treatment compared to tumors that continued to grow uninhibited. Additionally, compared to resistant tumors, DOX sensitive tumors contained significantly more CD4 T helper cells (339%), γδ T cells (727%), Naïve T cells (278%), and activated CD8 T cells (130%). Furthermore, transcriptional profiles of tumor infiltrated T cells in DOX responsive tumors revealed decreased exhaustion, increased chemokine/cytokine expression, and increased activation and cytotoxic activity. γδ T cell derived IL-17A was identified to be highly abundant in the sensitive tumor microenvironment. IL-17A was also found to directly increase sensitivity of TNBC cells in combination with DOX treatment. In TNBC tumors sensitive to DOX, increased IL-17A levels lead to a direct effect on cancer cell responsiveness and chronic stimulation of tumor infiltrated T cells leading to improved chemotherapeutic efficacy. IL-17A's role as a chemosensitive cytokine in TNBC may offer new opportunities for treating chemoresistant breast tumors and other cancer types.
Insights
Triple negative breast cancer (TNBC) treatment with doxorubicin (DOX) shows varied efficacy. Increased T cells, particularly γδ T cells producing IL-17A, enhance DOX sensitivity and improve chemotherapy outcomes.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Triple negative breast cancer (TNBC) presents significant treatment challenges due to a lack of targetable receptors and high intertumoral heterogeneity.
- Doxorubicin (DOX) is a common neoadjuvant chemotherapy for TNBC, but its efficacy varies widely among patients.
- Understanding the factors influencing differential responses to DOX is crucial for improving treatment strategies.
Purpose of the Study:
- To investigate the immune microenvironment changes associated with differential responses to doxorubicin (DOX) in triple negative breast cancer (TNBC).
- To identify specific immune cell populations and molecular mechanisms contributing to DOX sensitivity or resistance in TNBC.
- To explore the potential of IL-17A as a therapeutic agent to enhance DOX efficacy in TNBC.
Main Methods:
- Utilized a 4T1 syngeneic mouse model of TNBC for a seven-day doxorubicin (DOX) treatment regimen.
- Employed single-cell RNA sequencing to analyze tumor-infiltrating immune cells in DOX-sensitive versus DOX-resistant tumors.
- Quantified specific T cell subsets (CD4, γδ, Naïve, CD8) and assessed their activation and functional states.
Main Results:
- DOX-responsive TNBC tumors exhibited a significant increase in T cell infiltration compared to resistant tumors.
- DOX-sensitive tumors showed higher proportions of CD4 T helper cells, γδ T cells, Naïve T cells, and activated CD8 T cells.
- Tumor-infiltrating T cells in sensitive tumors displayed reduced exhaustion, increased cytokine/chemokine expression, and enhanced cytotoxic activity, with γδ T cell-derived IL-17A being notably abundant.
Conclusions:
- Increased IL-17A levels in the tumor microenvironment directly enhance TNBC cell sensitivity to DOX.
- IL-17A promotes T cell stimulation, leading to improved chemotherapeutic efficacy in DOX-sensitive TNBC.
- IL-17A represents a potential therapeutic target for overcoming chemoresistance in breast cancer and other malignancies.
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