Nasraa Mohamed Hassan, Bahgat Mahmoud Mohamed, Kirschfinik Michael
Department of Therapeutic Chemistry, Institute of Pharmaceutical and Drug Industries Research, The National Research Centre, Dokki, Cairo, 12622, Egypt.
Egypt Center for Research and Regenerative Medicine, Cairo, Egypt.
Med Oncol. 2025 Jun 19;42(7):275. doi: 10.1007/s12032-025-02832-z.
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 are 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 understand challenges posed by drug resistance in breast cancer treatment where 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 opserveded. Both cell lines were treated with different concentrations of each drug for 24 and 48 h, followed by evaluating 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 though this work is limited to HER2-positive breast cancer cell lines, short-term exposure to chemotherapeutics enhanced their resistance to CDC. However, since they are efficiently opsonized with the iC3b, this could increase their vulnerability to immunological attacks by CDCC) and ADCC. Such unique contribution illuminates a previously unnoticed shift in the immune elimination landscape following chemotherapy and opens doors for enhancing combination immunotherapies.
癌细胞对免疫介导杀伤的抗性在优化治疗策略以及将化疗、放疗和免疫治疗期间的不良反应降至最低方面构成了重大挑战。因此，迫切需要探索新的生物标志物，以评估和监测癌症治疗反应、早期检测毒性副作用并指导个体化治疗。我们开展这项研究是为了加深对乳腺癌治疗中耐药性所带来挑战的理解，观察了用盐酸多柔比星（多柔比星）和紫杉醇（紫杉醇）对BT - 474和SKBR - 3乳腺癌细胞系进行预处理对补体依赖性细胞毒性（CDC）和调理作用的影响。两种细胞系均用每种药物的不同浓度处理24小时和48小时，随后评估膜结合补体调节蛋白（mCRP）的表达、因子H（fH）结合、iC3b调理作用以及CDC介导的细胞杀伤。化疗药物预处理导致mCRP（CD46、CD55、CD59）出现不同程度的上调以及fH结合增加，这导致两个时间点的癌细胞裂解减少。相反，在暴露于任何一种药物48小时后，iC3b调理作用增强。尽管这项工作仅限于HER2阳性乳腺癌细胞系，但我们的数据表明，虽然这项工作仅限于HER2阳性乳腺癌细胞系，但短期暴露于化疗药物会增强它们对CDC的抗性。然而，由于它们能被iC3b有效调理，这可能会增加它们对CDCC和ADCC免疫攻击的易感性。这种独特的作用揭示了化疗后免疫清除格局中一个先前未被注意到的转变，并为增强联合免疫治疗开辟了道路。
