In spite of impressive results in the treatment of acute lymphoblastic B cell leukemia (B-ALL) with chimeric antigen receptor (CAR) T cells, the clinical outcome of some hematological cancers like follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) has not been very promising likely due to immunosuppressive networks within tumor microenvironment. Hypoxia in the microenvironment of hematological malignancies and consequently generation of adenosine molecule is appeared to be correlated with immunosuppression, tumor progression, and relapse. Herein, we hypothesized that whether pharmacological targeting of adenosine 2a receptor (A2aR) can enhance antitumor activity of anti-CD19 CAR T cells in vitro. Prior to functional assays, A2aR expression was assessed in CAR-expressing T cells. Our results showed that A2aR was not only up-regulated in the fully human anti-CD19 CAR T cells (hereafter referred to as huCAR19 T cells) but also was further overexpressed following re-stimulation with target cells. Although pharmacological inhibition of A2aR could significantly increase proliferation capacity and cytokine production of huCAR19 T cells following treatment with an adenosine analog, cytotoxic activity of huCAR19 T cells was not significantly improved. Considering A2aR overexpression in huCAR19 T cells in the tumor microenvironment, our results indicated that pharmacological targeting of A2aR could not only improve huCAR19 T cells functionality in a hostile tumor microenvironment but also could have a therapeutic advantage, and sought to assess the possibility in a pre-clinical setting.

中文翻译：

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免疫检查点A2aR的药理靶向可改善抗CD19 CAR T细胞的体外功能。

尽管用嵌合抗原受体（CAR）T细胞治疗急性淋巴细胞性B细胞白血病（B-ALL）取得了令人印象深刻的结果，但某些血液系统癌如滤泡性淋巴瘤（FL）和慢性淋巴细胞性白血病（CLL）的临床结果由于肿瘤微环境中的免疫抑制网络，其前景不太乐观。血液系统恶性肿瘤的微环境中的缺氧以及因此腺苷分子的产生似乎与免疫抑制，肿瘤进展和复发相关。在本文中，我们假设腺苷2a受体（A2aR）的药理靶向能否增强体外抗CD19 CAR T细胞的抗肿瘤活性。在进行功能测定之前，先评估表达CAR的T细胞中的A2aR表达。我们的结果表明，A2aR不仅在完全人类抗CD19 CAR T细胞（以下称为huCAR19 T细胞）中上调，而且在用靶细胞重新刺激后进一步过表达。尽管用腺苷类似物处理后，A2aR的药理抑制作用可以显着增加huCAR19 T细胞的增殖能力和细胞因子的产生，但huCAR19 T细胞的细胞毒性活性并未得到明显改善。考虑到肿瘤微环境中huCAR19 T细胞中A2aR的过表达，我们的结果表明，针对A2aR的药理作用不仅可以改善敌对肿瘤微环境中huCAR19 T细胞的功能，而且还可以具有治疗优势，并试图评估前期治疗的可能性。 -临床上。