Modeling Immunotherapy in Ex Vivo Organ Culture of Non-Small Cell Lung Cancer (Nsclc)

Jair Bar,Inbal Daniel-Meshulam,Amir Onn,Alon Ben-Nun,David Simansky,Nona Zeitlin,Nir Golan,Meirav Rokah,Ronni Ben-Avi,Iris Kamer

Cancer Research（2016）SCI 1区

Sheba Medical Ctr. Inst. of Oncology

Cited 0|Views38

Abstract

Abstract PD1-PDL1 interaction is one mechanism of tumor evasion of the immune system, and inhibitors of this interaction can allow cancer cell killing by cytotoxic T cells. In NSCLC as well as in most other cancers, the clinical benefit from such inhibitors is far from universal; around 20% of tumors respond to this treatment. Response of tumors to anti-cancer agents depends on interactions of epithelial tumor cells and the microenvironment, including stromal cells such as fibroblasts, immune cells and extracellular matrix. Studying cell signaling and drug-sensitivity of cancer should take into consideration the different compartments of an individual tumor. Regarding immunotherapy, manipulating regulators of PDL1 expression might augment the activity of these drugs, or possibly be active as an immunotherapy on its own. Specifically, little is known about the impact of chemotherapy, radiotherapy or targeted agents on the expression and activity of the PD1-PDL1 signaling in human cancer. Combining such treatments with immunotherapy is a potentially promising approach that is currently investigated clinically. However, the number of potential combinations is vast, and no valid and convenient experimental model exists to test candidate treatments and combinations. Experimental procedures: Ex vivo organ cultures (EVOC) were directly established from fresh NSCLC tissues, as a model that recapitulates real tumor and its microenvironment, including immune cells. Tissue elements were mechanistically dispersed to cell clumps (30-100 cells per clump), or cut to one cubic mm pieces and placed in culture. LDH release was used as a surrogate of cell death. Samples were analyzed by formalin fixation and paraffin embedment, sectioning and hematoxilin and eosin visualization of cells. PDL1 mRNA and protein levels were measured by RT-PCR and western blots. Results: Cell viability of NSCLC EVOC is maintained over a time window of at least 4-7 days. Cytotoxic drugs evoke cell death. PDL1 mRNA and protein levels are elevated in NSCLC EVOC in response to inflammation signals as Interferon gamma. Glucocorticoid steroidal drugs causes reduction in PDL1 mRNA and protein in NSCLC EVOC. Cisplatin treatment causes elevation in PDL1 protein. Variability in basal and induced PDL1 protein levels was detected in response to inflammation signals in EVOCs generated from different patients. Conclusions: Our results indicate the feasibility of EVOC for NSCLC and the potential to use it as a model to study the impact of immunotherapy agents, alone or in combination with other therapeutic tools such as chemotherapy or radiotherapy. Citation Format: Jair Bar, Inbal Daniel-Meshulam, Amir Onn, Alon Ben-Nun, David Simansky, Nona Zeitlin, Nir Golan, Meirav Rokah, Ronni Ben-Avi, Iris Kamer. Modeling immunotherapy in ex vivo organ culture of non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4910.

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【要点】：该研究提出了一种利用体外器官培养模型（EVOC）来模拟非小细胞肺癌（NSCLC）免疫治疗的效果，并探索了化疗、放疗与免疫治疗的联合应用潜力。

【方法】：研究通过将新鲜NSCLC组织直接建立为体外器官培养模型，模拟真实的肿瘤和其微环境，包括免疫细胞。

【实验】：实验通过将组织机械分散成细胞团（每团30-100个细胞）或切成1立方毫米的块状物并在培养中进行，使用LDH释放作为细胞死亡的替代指标，通过RT-PCR和Western blot测量PDL1 mRNA和蛋白质水平。结果显示，NSCLC EVOC的细胞存活时间至少为4-7天，并且细胞死亡由细胞毒性药物引起。PDL1 mRNA和蛋白质水平在炎症信号如干扰素γ作用下升高，糖皮质激素类药物导致PDL1 mRNA和蛋白质水平下降，而顺铂治疗导致PDL1蛋白质水平升高。不同患者来源的EVOCs对炎症信号的PDL1蛋白质水平基础和诱导变化存在差异。