Department of Cell Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany.
Cancer Immunol Res. 2022 Dec 2;10(12):1462-1474. doi: 10.1158/2326-6066.CIR-22-0113.
Cytotoxic T lymphocytes (CTL) are antigen-specific effector cells with the ability to eradicate cancer cells in a contact-dependent manner. Metabolic perturbation compromises the CTL effector response in tumor subregions, resulting in failed cancer cell elimination despite the infiltration of tumor-specific CTLs. Restoring the functionality of these tumor-infiltrating CTLs is key to improve immunotherapy. Extracellular adenosine is an immunosuppressive metabolite produced within the tumor microenvironment. Here, by applying single-cell reporter strategies in 3D collagen cocultures in vitro and progressing tumors in vivo, we show that adenosine weakens one-to-one pairing of activated effector CTLs with target cells, thereby dampening serial cytotoxic hit delivery and cumulative death induction. Adenosine also severely compromised CTL effector restimulation and expansion. Antagonization of adenosine A2a receptor (ADORA2a) signaling stabilized and prolonged CTL-target cell conjugation and accelerated lethal hit delivery by both individual contacts and CTL swarms. Because adenosine signaling is a near-constitutive confounding parameter in metabolically perturbed tumors, ADORA2a targeting represents an orthogonal adjuvant strategy to enhance immunotherapy efficacy.
细胞毒性 T 淋巴细胞（CTL）是具有特异性抗原识别能力的效应细胞，能够以接触依赖的方式消灭癌细胞。代谢紊乱会影响肿瘤亚区 CTL 的效应反应，导致尽管肿瘤特异性 CTL 浸润，但仍无法消除癌细胞。恢复这些浸润肿瘤的 CTL 的功能是改善免疫疗法的关键。细胞外腺苷是肿瘤微环境中产生的一种免疫抑制代谢物。在这里，我们通过在体外 3D 胶原共培养物中应用单细胞报告策略以及体内进展的肿瘤，表明腺苷减弱了激活的效应 CTL 与靶细胞的一对一配对，从而抑制了连续的细胞毒性打击传递和累积的诱导死亡。腺苷还严重损害了 CTL 效应细胞的再刺激和扩增。腺苷 A2a 受体（ADORA2a）信号的拮抗稳定并延长了 CTL-靶细胞的共轭，并通过单个接触和 CTL 群加速了致命打击的传递。由于腺苷信号是代谢紊乱肿瘤中近乎组成性的混杂参数，因此 ADORA2a 靶向代表了增强免疫疗法疗效的正交辅助策略。
