Razmara Aryana M, Judge Sean J, Gingrich Alicia A, Cruz Sylvia M, Culp William T N, Kent Michael S, Rebhun Robert B, Canter Robert J
Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States.
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
Front Vet Sci. 2021 Nov 16;8:771737. doi: 10.3389/fvets.2021.771737. eCollection 2021.
Metastatic osteosarcoma has a bleak prognosis in both humans and dogs, and there have been minimal therapeutic advances in recent decades to improve outcomes. Naturally occurring osteosarcoma in dogs is shown to be a highly suitable model for human osteosarcoma, and limited data suggest the similarities between species extend into immune responses to cancer. Studies show that immune infiltrates in canine osteosarcoma resemble those of human osteosarcoma, and the analysis of tumor immune constituents as predictors of therapeutic response is a promising direction for future research. Additionally, clinical studies in dogs have piloted the use of NK transfer to treat osteosarcoma and can serve as valuable precursors to clinical trials in humans. Cytotoxic lymphocytes in dogs and humans with osteosarcoma have increased activation and exhaustion markers within tumors compared with blood. Accordingly, NK and T cells have complex interactions among cancer cells and other immune cells, which can lead to changes in pathways that work both for and against the tumor. Studies focused on NK and T cell interactions within the tumor microenvironment can open the door to targeted therapies, such as checkpoint inhibitors. Specifically, PD-1/PD-L1 checkpoint expression is conserved across tumors in both species, but further characterization of PD-L1 in canine osteosarcoma is needed to assess its prognostic significance compared with humans. Ultimately, a comparative understanding of T and NK cells in the osteosarcoma tumor microenvironment in both dogs and humans can be a platform for translational studies that improve outcomes in both dogs and humans with this frequently aggressive disease.
转移性骨肉瘤在人类和犬类中预后都很严峻，近几十年来治疗进展甚微，难以改善治疗结果。犬类自然发生的骨肉瘤被证明是人类骨肉瘤的高度合适模型，有限的数据表明物种间的相似性延伸到对癌症的免疫反应。研究表明，犬类骨肉瘤中的免疫浸润与人类骨肉瘤相似，将肿瘤免疫成分分析作为治疗反应的预测指标是未来研究的一个有前景的方向。此外，犬类的临床研究已率先使用自然杀伤细胞（NK）转移来治疗骨肉瘤，可作为人类临床试验的宝贵先导。与血液相比，患有骨肉瘤的犬类和人类肿瘤内的细胞毒性淋巴细胞具有更高的激活和耗竭标志物。因此，NK细胞和T细胞在癌细胞与其他免疫细胞之间存在复杂的相互作用，这可能导致对肿瘤起促进和抑制作用的信号通路发生变化。专注于肿瘤微环境中NK细胞和T细胞相互作用的研究可为靶向治疗（如检查点抑制剂）打开大门。具体而言，两种物种的肿瘤中PD-1/PD-L1检查点表达均保守，但需要对犬类骨肉瘤中的PD-L1进行进一步表征，以评估其与人类相比的预后意义。最终，对犬类和人类骨肉瘤肿瘤微环境中T细胞和NK细胞的比较理解可成为转化研究的平台，改善患有这种常见侵袭性疾病的犬类和人类的治疗结果。
