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Triple-Negative Breast Cancer Cells Utilize IL8 and CXCL1 to Suppress NK Cells' Function and Facilitate Cancer
Mingheng Yuan1, Hongmei Yang1, Renfei Wu1
1Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China.
Abstract:
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with high metastatic potential and limited treatment options. Natural killer (NK) cells represent a promising immunotherapy strategy due to their innate tumor-killing capacity, but their efficacy against TNBC remains limited. We found that TNBC cells, particularly the mesenchymal-like subtype, exhibited greater resistance to NK cells compared to non-TNBC cells. Mechanistic studies indicate that TNBC cells' survival in response to NK cells occurs in three phases. First, within 1 h of NK cell co-culture, TNBC cells accumulate reactive oxygen species (ROS), which upregulate C-X-C motif chemokine ligand 1 (CXCL1) and interleukin 8 (IL8) expression in an NF-κB- and ERK/JNK-AP-1-dependent manner. Second, secreted CXCL1/IL8 binds to C-X-C motif chemokine receptor 1/2 (CXCR1/2), activating the AKT-BCL-2 pathway to enhance cancer cell survival and suppress NK cell function by downregulating NKG2D, TRAIL, and IFN-γ expression. Third, CXCL1/IL8-CXCR1/2 autocrine loop further amplifies their own synthesis and induces programmed cell death 1 ligand 1 (PD-L1) expression via NF-κB and ERK/JNK-AP-1 pathways. High CXCL1/IL8 expression correlates with reduced NK cell infiltration and shorter distant-metastasis-free survival in breast cancer patients. Combinatorial application of CXCR1/2 inhibitor with anti-PD-L1 antibody can overcome NK cell dysfunction and reduce TNBC metastasis.
Insights
Triple-negative breast cancer (TNBC) resists natural killer (NK) cell immunotherapy. TNBC cells secrete CXCL1/IL8, which suppresses NK cells and promotes tumor growth, but blocking CXCR1/2 and PD-L1 can overcome this resistance.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with poor treatment options.
- Natural killer (NK) cells show promise for immunotherapy but are limited against TNBC.
- TNBC, especially mesenchymal subtypes, exhibits resistance to NK cell-mediated killing.
Purpose of the Study:
- To elucidate the mechanisms by which TNBC evades NK cell surveillance.
- To identify therapeutic targets for enhancing NK cell efficacy against TNBC.
- To investigate the role of CXCL1/IL8 and PD-L1 in TNBC immune evasion.
Main Methods:
- Co-culture of TNBC and NK cells.
- Analysis of reactive oxygen species (ROS) and cytokine/chemokine expression (CXCL1, IL8).
- Investigation of signaling pathways (NF-κB, ERK/JNK-AP-1, AKT-BCL-2).
- Assessment of NK cell receptor expression (NKG2D, TRAIL) and function.
- Correlation of CXCL1/IL8 levels with patient survival and NK cell infiltration.
- Evaluation of combination therapy (CXCR1/2 inhibitor and anti-PD-L1 antibody).
Main Results:
- TNBC cells accumulate ROS, upregulating CXCL1/IL8 via NF-κB and ERK/JNK-AP-1 pathways.
- Secreted CXCL1/IL8 activates AKT-BCL-2, enhancing TNBC survival and suppressing NK cell function (downregulating NKG2D, TRAIL, IFN-γ).
- An autocrine CXCL1/IL8-CXCR1/2 loop amplifies cytokine production and induces PD-L1 expression.
- High CXCL1/IL8 correlates with reduced NK cell infiltration and poorer distant-metastasis-free survival.
- Combination therapy with a CXCR1/2 inhibitor and anti-PD-L1 antibody restored NK cell function and reduced TNBC metastasis.
Conclusions:
- TNBC employs a multi-phase mechanism involving ROS, CXCL1/IL8, and PD-L1 to evade NK cell immunity.
- The CXCL1/IL8-CXCR1/2 axis and PD-L1 are critical mediators of TNBC immune evasion and metastasis.
- Targeting the CXCR1/2 and PD-L1 pathways offers a promising combinatorial strategy to enhance immunotherapy for TNBC.
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