Department of Pharmaceutics, Rutgers University, 160 Frelinghuysen Road, Piscataway, NJ, 08854-8020, USA.
Cancer Pharmacology Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.
Med Oncol. 2023 Mar 2;40(4):110. doi: 10.1007/s12032-023-01975-1.
Cancer stem-like cells (CSCs) are believed to be responsible for cancer recurrence and metastasis. Therefore, a therapeutic approach is needed to eliminate both rapidly proliferating differentiated cancer cells and slow-growing drug-resistant CSCs. Using established ovarian cancer cells lines as well as ovarian cancer cells isolated from a patient with high-grade drug-resistant ovarian carcinoma, we demonstrate that ovarian CSCs consistently express lower levels of NKG2D ligands (MICA/B and ULBPs) on their surfaces, a mechanism by which they evade natural killer (NK) cells' surveillance. Here, we discovered that exposure of ovarian cancer (OC) cells to SN-38 followed by 5-FU not only acts synergistically to kill the OC cells, but also makes the CSCs vulnerable to NK92 cells through upregulation of NKG2D ligands. Since systemic administration of these two drugs is marred by intolerance and instability, we engineered and isolated an adipose-derived stem cell (ASC) clone, which stably expresses carboxylesterase-2 and yeast cytosine deaminase enzymes to convert irinotecan and 5-FC prodrugs into SN-38 and 5-FU cytotoxic drugs, respectively. Co-incubation of ASCs and prodrugs with drug-resistant OC cells not only led to the death of the drug-resistant OC cells but also made them significantly vulnerable to NK92 cells. This study provides proof of principle for a combined ASC-directed targeted chemotherapy with NK92-assisted immunotherapy to eradicate drug-resistant OC cells.
癌症干细胞（CSC）被认为是导致癌症复发和转移的罪魁祸首。因此，需要一种治疗方法来消除快速增殖的分化癌细胞和生长缓慢的耐药 CSC。我们使用已建立的卵巢癌细胞系以及从一位患有高级耐药卵巢癌的患者中分离出的卵巢癌细胞，证明卵巢 CSC 表面始终表达较低水平的 NKG2D 配体（MICA/B 和 ULBPs），这是它们逃避自然杀伤（NK）细胞监测的一种机制。在这里，我们发现将 SN-38 暴露于卵巢癌细胞（OC）后再用 5-FU 处理，不仅能协同杀死 OC 细胞，还能通过上调 NKG2D 配体使 CSC 对 NK92 细胞变得脆弱。由于这两种药物的全身给药存在不耐受和不稳定性问题，我们设计并分离了一个脂肪来源的干细胞（ASC）克隆，该克隆稳定表达羧酯酶-2 和酵母胞嘧啶脱氨酶酶，分别将伊立替康和 5-FC 前药转化为 SN-38 和 5-FU 细胞毒性药物。将 ASC 和前药与耐药 OC 细胞共孵育不仅导致耐药 OC 细胞死亡，而且使它们对 NK92 细胞明显变得脆弱。这项研究为 ASC 定向靶向化疗与 NK92 辅助免疫治疗相结合以根除耐药 OC 细胞提供了原理证明。
