IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer
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 tumormore »
- Authors:
- Publication Date:
- Research Org.:
- Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program; National Cancer Institute (NCI)
- OSTI Identifier:
- 1876525
- Alternate Identifier(s):
- OSTI ID: 1894007
- Report Number(s):
- LLNL-JRNL-830154
Journal ID: ISSN 2234-943X; 928474
- Grant/Contract Number:
- AC52-07NA27344; NCI P30CA093373
- Resource Type:
- Published Article
- Journal Name:
- Frontiers in Oncology
- Additional Journal Information:
- Journal Name: Frontiers in Oncology Journal Volume: 12; Journal ID: ISSN 2234-943X
- Publisher:
- Frontiers Media SA
- Country of Publication:
- Switzerland
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; triple negative breast cancer; doxorubicin; IL-17A, gd T cells; chemoresistance; 4T1; single cell RNA seq
Citation Formats
Hum, Nicholas R., Sebastian, Aimy, Martin, Kelly A., Rios-Arce, Naiomy D., Gilmore, Sean F., Gravano, David M., Wheeler, Elizabeth K., Coleman, Matthew A., and Loots, Gabriela G. IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer. Switzerland: N. p., 2022.
Web. doi:10.3389/fonc.2022.928474.
Hum, Nicholas R., Sebastian, Aimy, Martin, Kelly A., Rios-Arce, Naiomy D., Gilmore, Sean F., Gravano, David M., Wheeler, Elizabeth K., Coleman, Matthew A., & Loots, Gabriela G. IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer. Switzerland. https://doi.org/10.3389/fonc.2022.928474
Hum, Nicholas R., Sebastian, Aimy, Martin, Kelly A., Rios-Arce, Naiomy D., Gilmore, Sean F., Gravano, David M., Wheeler, Elizabeth K., Coleman, Matthew A., and Loots, Gabriela G. Mon .
"IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer". Switzerland. https://doi.org/10.3389/fonc.2022.928474.
@article{osti_1876525,
title = {IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer},
author = {Hum, Nicholas R. and Sebastian, Aimy and Martin, Kelly A. and Rios-Arce, Naiomy D. and Gilmore, Sean F. and Gravano, David M. and Wheeler, Elizabeth K. and Coleman, Matthew A. and Loots, Gabriela G.},
abstractNote = {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.},
doi = {10.3389/fonc.2022.928474},
journal = {Frontiers in Oncology},
number = ,
volume = 12,
place = {Switzerland},
year = {Mon Jul 18 00:00:00 EDT 2022},
month = {Mon Jul 18 00:00:00 EDT 2022}
}
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