肿瘤细胞治疗研究
英文原题：IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts.
IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts.
我们揭示CD70在血液肿瘤和实体瘤中均是一个有吸引力的靶点。经IL-15武装的CAR NK细胞可作为强效效应细胞清除这些CD70+细胞。它们可靶向CRC和PDAC患者的肿瘤细胞和CAFs，并可能靶向其他促结缔组织增生性实体瘤。
在结直肠癌（CRC）和胰腺导管腺癌（PDAC）等实体恶性肿瘤中，利用嵌合抗原受体（CAR）工程化细胞疗法取得阳性结果仍然具有挑战性。一个主要障碍是缺乏不被健康组织共享的可靶向表面抗原。CD70因其在健康组织中的严格表达模式以及在相当多恶性肿瘤中对肿瘤进展的明显作用，成为一个有趣的靶点。此外，CD70也表达于癌症相关成纤维细胞（CAFs），这是CRC和PDAC治疗疗效的另一个障碍。我们探索了CD70作为CAR自然杀伤（NK）细胞疗法靶点在CRC、PDAC中的治疗潜力，重点关注肿瘤细胞和CAFs，以及淋巴瘤。
使用RNA-seq数据和患者样本的免疫组化分析来探究CRC和PDAC患者中CD70的表达。此外，开发了靶向CD70的CAR NK细胞，以评估其对CD70+肿瘤细胞和CAFs的细胞毒性活性，并评价细胞因子刺激对其疗效的影响。在体外研究了CD70-CAR NK细胞对一组具有不同CD70表达的肿瘤和CAF细胞系的功能。使用荷淋巴瘤小鼠验证CD70-CAR NK细胞的体内效力。最后，为考虑患者变异性，在含有CAFs的患者来源类器官上测试了CD70-CAR NK细胞。
在本研究中，我们确定 CD70 是 CRC 和 PDAC 患者中肿瘤细胞和 CAFs 的靶点。对靶向 CD70 的 CAR NK 细胞进行功能评估表明，IL-15 刺激对于有效清除 CD70+ 肿瘤细胞和 CAFs，以及改善荷 CD70+ 肿瘤小鼠的肿瘤负荷和生存至关重要。在机制上，IL-15 刺激通过上调 CAR 表达并以主要自分泌或细胞内方式增加促炎细胞因子的分泌，从而提高了 CD70-CAR NK 细胞的效力。
BACKGROUND: It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma. METHODS: RNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70 + tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs. RESULTS: In this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70 + tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70 + tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner. CONCLUSIONS: We disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70 + cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors.
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