Journal
MOLECULAR ONCOLOGY
Volume 16, Issue 3, Pages 594-606Publisher
WILEY
DOI: 10.1002/1878-0261.13088
Keywords
ER stress; IRES; ITAF; long noncoding RNA; melanoma; tumor antigens
Categories
Funding
- Ligue Regionale Contre le Cancer Grand Ouest (France)
- Biogenouest, Infrastructures en Biologie Sante et Agronomie (IBiSA)
- Conseil Regional de Bretagne
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The main challenge in cancer immunotherapy is selecting relevant tumor antigens. The study investigates the translation control of MELOE-1 and its role in melanoma cells. It shows that promoting hnRNP-A1 translation in tumor cells enhances MELOE-1 recognition and the efficacy of immunotherapies.
The major challenge in antigen-specific immunotherapy of cancer is to select the most relevant tumor antigens to target. To this aim, understanding their mode of expression by tumor cells is critical. We previously identified a melanoma-specific antigen, melanoma-overexpressed antigen 1 (MELOE-1)-coded for by a long noncoding RNA-whose internal ribosomal entry sequence (IRES)-dependent translation is restricted to tumor cells. This restricted expression is associated with the presence of a broad-specific T-cell repertoire that is involved in tumor immunosurveillance in melanoma patients. In the present work, we explored the translation control of MELOE-1 and provide evidence that heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) binds to the MELOE-1 IRES and acts as an IRES trans-activating factor (ITAF) to promote the translation of MELOE-1 in melanoma cells. In addition, we showed that endoplasmic reticulum (ER) stress induced by thapsigargin, which promotes hnRNP-A1 cytoplasmic translocation, enhances MELOE-1 translation and recognition of melanoma cells by a MELOE-1-specific T-cell clone. These findings suggest that pharmacological stimulation of stress pathways may enhance the efficacy of immunotherapies targeting stress-induced tumor antigens such as MELOE-1.
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