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. Recent studies uncovered a role for MAGEA6 in suppression of macroautophagy/autophagy implicating MAGEA6 in tumorigenesis. The impact of cancer-associated MAGEA6 mutations on tumor pathophysiology are less well explored. In pancreatic cancer cell models, MAGEA6 inhibits autophagy, facilitating pancreatic cancer initiation. However, autophagy places a brake on cancer progression and is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations that reinstitute autophagy. Further cancer-associated mutations of the broader MAGEA genes frequently result in degradation of the corresponding protein products by proteasome-dependent machinery, potentially jeopardizing the utility of MAGEA genes as immunotherapeutic targets. Altogether, our findings provide mechanistic insight into the divergent roles of MAGEA6 during pancreatic cancer initiation and progression, and could inform cancer immunotherapeutic strategies for targeting MAGEA antigens.

黑色素瘤相关抗原家族 A (MAGEA) 抗原在多种恶性肿瘤中表达，但在成人体细胞中不表达，使它们成为癌症免疫治疗的有吸引力的靶点。最近的研究揭示了MAGEA6在抑制巨自噬/自噬中的作用，这表明MAGEA6与肿瘤发生有关。癌症相关MAGEA6的影响对肿瘤病理生理学突变的研究较少。在胰腺癌细胞模型中，MAGEA6 抑制自噬，促进胰腺癌的发生。然而，自噬会阻止癌症进展，并在 MAGEA6 降解时释放，这可以由营养缺乏或获得重新启动自噬的癌症相关突变引起。更广泛的MAGEA基因的进一步癌症相关突变经常导致相应的蛋白质产物被蛋白酶体依赖性机制降解，从而可能危及MAGEA基因作为免疫治疗靶点的效用。总而言之，我们的研究结果提供了对MAGEA6不同作用的机械洞察 在胰腺癌的发生和发展过程中，并且可以为靶向 MAGEA 抗原的癌症免疫治疗策略提供信息。