IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer

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.

doi:10.3389/fonc.2022.928474

Title: IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer

Journal Article · Mon Jul 18 00:00:00 EDT 2022 · Frontiers in Oncology

DOI:https://doi.org/10.3389/fonc.2022.928474· OSTI ID:1876525

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.

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.

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Research Organization:: Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program; National Cancer Institute (NCI)

Grant/Contract Number:: AC52-07NA27344; NCI P30CA093373

OSTI ID:: 1876525

Alternate ID(s):: OSTI ID: 1894007

Report Number(s):: LLNL-JRNL-830154; 928474

Journal Information:: Frontiers in Oncology, Journal Name: Frontiers in Oncology Vol. 12; ISSN 2234-943X

Publisher:: Frontiers Media SACopyright Statement

Country of Publication:: Switzerland

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
triple negative breast cancer
doxorubicin
IL-17A
gd T cells
chemoresistance
4T1
single cell RNA seq

Title: IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer

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