Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
Cell, Develop & Cancer Biology, Oregon Health & Science University, Portland, United States.
Elife. 2020 Apr 9;9:e48963. doi: 10.7554/eLife.48963.
The melanoma-associated antigen family A (MAGEA) antigens are expressed in a wide variety of malignant tumors but not in adult somatic cells, rendering them attractive targets for cancer immunotherapy. Here we show that a number of cancer-associated MAGEA mutants that undergo proteasome-dependent degradation in vitro could negatively impact their utility as immunotherapeutic targets. Importantly, in pancreatic ductal adenocarcinoma cell models, MAGEA6 suppresses macroautophagy (autophagy). The inhibition of autophagy is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations. Using xenograft mouse models, we demonstrated that inhibition of autophagy is critical for tumor initiation whereas reinstitution of autophagy as a consequence of MAGEA6 degradation contributes to tumor progression. These findings could inform cancer immunotherapeutic strategies for targeting MAGEA antigens and provide mechanistic insight into the divergent roles of during pancreatic cancer initiation and progression.
黑色素瘤相关抗原家族 A（MAGEA）抗原在多种恶性肿瘤中表达，但不在成年体细胞中表达，这使得它们成为癌症免疫治疗的有吸引力的靶标。在这里，我们表明，一些在体外经历蛋白酶体依赖性降解的与癌症相关的 MAGEA 突变体可能会对它们作为免疫治疗靶标的用途产生负面影响。重要的是，在胰腺导管腺癌细胞模型中，MAGEA6 抑制巨自噬（自噬）。自噬的抑制在 MAGEA6 降解时释放，这可以通过营养缺乏或获得与癌症相关的突变来诱导。使用异种移植小鼠模型，我们证明了自噬的抑制对于肿瘤起始至关重要，而由于 MAGEA6 降解导致的自噬的重新建立有助于肿瘤进展。这些发现可以为针对 MAGEA 抗原的癌症免疫治疗策略提供信息，并为在胰腺癌起始和进展过程中 MAGEA 的不同作用提供机制见解。
