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<p>Resistance of cancer cells to immune-mediated killing poses a significant challenge in optimizing therapeutic strategies and minimizing adverse effects during chemotherapy, radiotherapy, and immunotherapy. Consequently, exploring novel biomarkers is critically needed to assess and monitor cancer treatment response, detect toxic side effects early, and guide individualized therapy. We conducted this research to enhance our understanding of challenges posed by drug resistance in breast cancer treatment, in which the impact of pretreatment of BT-474 and SKBR-3 breast cancer cell lines with doxorubicin hydrochloride (doxorubicin) and paclitaxel (taxol) on complement-dependent cytotoxicity (CDC) and opsonization was observed. Both cell lines were treated with different concentrations of each drug for 24 and 48 h, followed by evaluation of the expression of membrane-bound complement regulatory proteins (mCRPs), factor H (fH) binding, iC3b opsonization, and cell killing by CDC. Pretreatment with chemotherapeutics led to variable upregulation of mCRPs (CD46, CD55, CD59) and increased fH binding, contributing to reduced cancer cell lysis at both time points. Conversely, iC3b opsonization was enhanced after 48 h of exposure to either drug. Though this work is limited to HER2-positive breast cancer cell lines, our data suggest that short-term exposure to chemotherapeutics enhances their resistance to CDC. However, since they are efficiently opsonized with iC3b, this could increase their vulnerability to immunological attacks by CDC and ADCC. Such a unique contribution illuminates a previously unnoticed shift in the immune elimination landscape following chemotherapy and opens doors for enhancing combination immunotherapies.</p>

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Chemotherapy of breast cancer cells alters susceptibility to complement-mediated opsonization and killing

  • 期刊论文

  • 发表日期：

    2025年6月19日

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  • Mohamed Hassan Nasraa,
  • Mahmoud Mohamed Bahgat,
  • Michael Kirschfinik

摘要

Resistance of cancer cells to immune-mediated killing poses a significant challenge in optimizing therapeutic strategies and minimizing adverse effects during chemotherapy, radiotherapy, and immunotherapy. Consequently, exploring novel biomarkers is critically needed to assess and monitor cancer treatment response, detect toxic side effects early, and guide individualized therapy. We conducted this research to enhance our understanding of challenges posed by drug resistance in breast cancer treatment, in which the impact of pretreatment of BT-474 and SKBR-3 breast cancer cell lines with doxorubicin hydrochloride (doxorubicin) and paclitaxel (taxol) on complement-dependent cytotoxicity (CDC) and opsonization was observed. Both cell lines were treated with different concentrations of each drug for 24 and 48 h, followed by evaluation of the expression of membrane-bound complement regulatory proteins (mCRPs), factor H (fH) binding, iC3b opsonization, and cell killing by CDC. Pretreatment with chemotherapeutics led to variable upregulation of mCRPs (CD46, CD55, CD59) and increased fH binding, contributing to reduced cancer cell lysis at both time points. Conversely, iC3b opsonization was enhanced after 48 h of exposure to either drug. Though this work is limited to HER2-positive breast cancer cell lines, our data suggest that short-term exposure to chemotherapeutics enhances their resistance to CDC. However, since they are efficiently opsonized with iC3b, this could increase their vulnerability to immunological attacks by CDC and ADCC. Such a unique contribution illuminates a previously unnoticed shift in the immune elimination landscape following chemotherapy and opens doors for enhancing combination immunotherapies.