Abstract

Background

Development of novel immunotherapeutics in oncology is of crucial interest and their good testing at preclinical stage relies on i) the features of the animal model used and ii) the application of an appropriate comprehensive strategy for the deep delineation of mechanisms underlying resistance/sensitivity to a drug.

Methods

Using a syngeneic sarcoma mouse model, treated with anti-PDL1, we investigated by intratumoral microdialysis and flow cytometry the immunometabolic profile and immune landscape of the tumour, respectively. The anti-tumor effect of PDL1 blockade was assessed through tumour growth monitoring and tumoral biopsies were also collected for gene expression analysis. Finally, involvement of CD8 T cells in the anti-tumour PDL1 blockade-mediated activity was addressed using a specific depleting antibody -based strategy.

Results

When compared to a non-tumour area, data obtained from tumour microdialysates highlighted i) a slight Kynurenine pathway activation, ii) a strong Arginase activity, and iii) a high Adenosine production. Interestingly, anti-PDL1 effect was associated with a decrease of the tumoral Adenosine level thus arguing for an important role of the Adenosine axis in the control of the anti-tumour immune response. In addition, PDL1 blockade led to an intratumoral CD45+ leukocytes enrichment, with a higher abundance of lymphocytes also displaying increased level of IFNgamma. In contrast, macrophages – CD11b+/F4:80+ - were limited upon treatment, especially the immunosuppressive CD11b/Gr1^Low/Int cellsubsets, in favor of an increase of the M1/M2 macrophages ratio. Interestingly, CD8 depletion fully abrogated anti-PDL1 anti-tumour effect thus showing the unequivocal role of this population. Finally, gene expression analysis revealed, in addition to an interferon signature, changes in genes from the myeloid / neutrophil subsets including Arg1 and key chemokines.

Conclusion

Altogether, this multiparametric dataset gives i) a better understanding of intrinsic features of the preclinical model and deeper insights into the mechanism of action of an effective drug, and ii) might serve as a platform combination-based strategy for comprehensive explorations of novel candidates.

Legal entity responsible for the study

Alban Bessede.

Funding

Explicyte Immuno-Oncology.

Disclosure

A. Bessede: Shareholder / Stockholder / Stock options, Full / Part-time employment: Explicyte. All other authors have declared no conflicts of interest.

中文翻译：

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134P在肉瘤小鼠模型中抗肿瘤PDL1阻断作用的综合评估

抽象的

背景

肿瘤学中新型免疫疗法的发展至关重要，其在临床前阶段的良好测试依赖于：i）所用动物模型的特征；和ii）应用适当的综合策略来深入描述对抗药性/敏感性的潜在机制。药品。

方法

使用同种肉瘤小鼠模型，用抗PDL1处理，我们通过肿瘤内微透析和流式细胞术分别研究了肿瘤的免疫代谢谱和免疫图谱。通过肿瘤生长监测评估了PDL1阻断的抗肿瘤作用，并收集了肿瘤活检样本进行基因表达分析。最后，使用特定的基于耗竭抗体的策略解决了CD8 T细胞参与抗肿瘤PDL1阻断介导的活性的问题。

结果

当与非肿瘤区域相比时，从肿瘤微透析液获得的数据突出显示了i）轻微的Kynurenine途径激活，ii）强大的精氨酸酶活性，和iii）高的腺苷生成量。有趣的是，抗PDL1的作用与肿瘤腺苷水平的降低有关，因此争论了腺苷轴在控制抗肿瘤免疫反应中的重要作用。此外，PDL1阻断导致肿瘤内CD45 +白细胞富集，淋巴细胞的丰度更高，也显示IFNgamma水平升高。相反，巨噬细胞– CD11b + / F4：80+ –受治疗限制，尤其是免疫抑制性CD11b / Gr1 ^{Low / Int}细胞集落，有利于增加M1 / M2巨噬细胞比例。有趣的是，CD8耗竭完全废除了抗PDL1的抗肿瘤作用，因此显示出该人群的明确作用。最后，基因表达分析显示，除干扰素签名外，髓样/中性粒细胞亚群（包括Arg1和关键趋化因子）的基因也发生了变化。

结论

总而言之，该多参数数据集使i）对临床前模型的内在特征有了更深入的了解，并对有效药物的作用机理有了更深入的了解，并且ii）可以作为基于平台组合的策略来全面探索新型候选药物。

负责研究的法人实体

奥尔本·贝塞德（Alban Bessede）。

资金

明确的免疫肿瘤学。

揭露

A. Bessede：股东/股东/股票期权，全职/兼职：显性。所有其他作者都声明没有利益冲突。