Background
Platinum-based chemotherapy has been the standard of care for metastasis in the past few decades. Herein, we aimed to develop a TETTargetFinder pipeline with a stepwise workflow to identify potential cell surface immune targets in mTETs.
Methods
From 2015 to 2020, 49 patients with stage IV TETs underwent clinical CLIA-based RNA sequencing. Using metastatic patients’ transcriptomic data, we developed an integrated cell surface computational platform that predicts cell surface protein expression. To overcome the limitation of bioinformatic prediction, immunohistochemistry (IHC) validated the presence of potential candidate proteins in a tissue array of 90 metastatic TETs and 35 normal tissues. We used spatial-transcriptomic analysis to assess the proximity of each potential target to T-cells in a separate cohort of four patients.
Results
From 60,908 transcriptomic pools of candidates, using the TETTargetFinder, in nine steps, 103 targets with high expression in TETs and low expression in normal tissues were identified. To achieve higher coverage, we performed IHC on top 10 targets that are overly expressed in thymoma and TC (ABCG1, ANO9, CLDND1, COL17A1, GRAMD1A, INFGR1, PLXNA3, SCLC30A5, SCLC7A6, and TTH3). COL17A1 showed the highest protein expression (IHC staining score: 0.79, SE 0.07) and it was significantly higher than Mesothelin as control (p= 0.04). COL17A1 was homogenously expressed in 66% of TETs with no expression in any vital organs. However, COL17A1 had med to high expression IHC expression in the skin epidermis. The spetial-transcriptomic analysis showed moderate proximity of T-cells with COL17A1. The thymoma top targets were ADCY3, CD96, EPHB6 and IGSF3 whereas TC-exclusive targets were ABHD12, ATC9A, ERBB2 and IL1R1.
Conclusion
We have developed a novel immune target discovery pipeline and found COL17A1 protein as a potential cell surface target in thymoma and TC. The limitation of this target is a mod-high expression in the skin epidermis. The precise identification of COL17A1 antibody epitope that is uniquely and exclusively present in thymic tumors, has the potential to serve as a crucial foundation for the development of targeted antibody-based therapeutic interventions.
