Immune checkpoint immunotherapy is a pillar of human oncology treatment with potential for non-human species. The first checkpoint immunotherapy approved for human cancers targeted the CTLA4 protein. CTLA4 can inhibit T cell activation by capturing and internalizing CD80 and CD86 from antigen presenting cells, a process called trans-endocytosis. Similarly, CD28 can capture CD80 and CD86 via trogocytosis and retain the captured ligands on the surface of the CD28-expressing cells. The wild Tasmanian devil (Sarcophilus harrisii) population has declined by 77% due to transmissible cancers that evade immune defenses despite genetic mismatches between the host and tumors. We used a live cell-based assay to demonstrate that devil CTLA4 and CD28 can capture CD80 and CD86. Mutation of evolutionarily conserved motifs in CTLA4 altered functional interactions with CD80 and CD86 in accordance with patterns observed in other species. These results suggest that checkpoint immunotherapies can be translated to evolutionarily divergent species.

免疫检查点免疫疗法是人类肿瘤治疗的支柱，具有非人类物种的潜力。第一个批准用于人类癌症的检查点免疫疗法靶向 CTLA4 蛋白。CTLA4 可以通过从抗原呈递细胞中捕获和内化 CD80 和 CD86 来抑制 T 细胞活化，这一过程称为反式内吞作用。类似地，CD28 可以通过吞噬作用捕获 CD80 和 CD86，并将捕获的配体保留在表达 CD28 的细胞表面。野生塔斯马尼亚恶魔 ( Sarcophilus harrisii) 人口减少了 77%，原因是尽管宿主和肿瘤之间存在基因不匹配，但仍会逃避免疫防御的传染性癌症。我们使用基于活细胞的测定来证明魔鬼 CTLA4 和 CD28 可以捕获 CD80 和 CD86。根据在其他物种中观察到的模式，CTLA4 中进化上保守的基序的突变改变了与 CD80 和 CD86 的功能相互作用。这些结果表明，检查点免疫疗法可以转化为进化上不同的物种。