癌症免疫治疗的生物标志物是一个未得到满足的医疗需求。 NKI 的 Daniela Thommen 小组最近报道了一种基于患者来源肿瘤碎片短期培养的新方法，其上清液中的细胞因子浓度和浸润 T 细胞上的激活标记物与 PD-1 阻断的临床反应相关。我们利用肿瘤衍生片段建立了类似的培养技术，将小鼠肿瘤移植到同基因免疫活性小鼠体内，以测试激动剂抗 CD137 mAb 及其与抗 PD-1 和/或抗 TGF-β 的组合。使用抗 CD137 和抗 PD-1 mAb 组合或刀豆球蛋白 A 作为阳性对照进行培养物激活后，检测到组织培养上清液中 IFNγ 浓度的增加。广泛的阵列中没有其他细胞因子能够提供这些单克隆抗体刺激的信息。有趣的是，72 小时培养结束时收集的细胞悬浮液中的淋巴细胞证实了 Ki67 和其他激活标记物的增加。在患有双侧肿瘤的小鼠中，在体内抗 CD137  抗 PD-1 治疗之前切除一个肿瘤以进行片段培养评估，没有发现片段产生的 IFNγ 与非小鼠体内治疗结果之间存在关联。切除对侧肿瘤。该实验系统允许冷冻和解冻具有相似功能结果的碎片。使用一系列来自切除的实体恶性肿瘤的患者来源的肿瘤碎片，我们在一小部分研究病例中显示了 IFNγ 的产生，这些碎片保存在冷冻/解冻的碎片中。小肿瘤碎片培养技术似乎适合临床前探索免疫治疗组合。© 2024 作者。经泰勒许可出版

Biomarkers for cancer immunotherapy are an unmet medical need. The group of Daniela Thommen at the NKI recently reported on novel methodologies based on short-term cultures of patient-derived tumor fragments whose cytokine concentrations in the supernatants and activation markers on infiltrating T cells were associated with clinical response to PD-1 blockade. We set up a similar culture technology with tumor-derived fragments using mouse tumors transplanted into syngeneic immunocompetent mice to test an agonist anti-CD137 mAb and its combinations with anti-PD-1 and/or anti-TGF-β. Increases in IFNγ concentrations in the tissue culture supernatants were detected upon in-culture activation with the anti-CD137 and anti-PD-1 mAb combinations or concanavalin A as a positive control. No other cytokine from a wide array was informative of stimulation with these mAbs. Interestingly, increases in Ki67 and other activation markers were substantiated in lymphocytes from cell suspensions gathered at the end of 72 h cultures. In mice bearing bilateral tumors in which one was excised prior to in vivo anti-CD137 + anti-PD-1 treatment to perform the fragment culture evaluation, no association was found between IFNγ production from the fragments and the in vivo therapeutic outcome in the non-resected contralateral tumors. The experimental system permitted freezing and thawing of the fragments with similar functional outcomes. Using a series of patient-derived tumor fragments from excised solid malignancies, we showed IFNγ production in a fraction of the studied cases, that was conserved in frozen/thawed fragments. The small tumor fragment culture technique seems suitable to preclinically explore immunotherapy combinations.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.