The roles of MAGEA6 variants in pancreatic cancer development and their potential impact on cancer immunotherapy

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.