Claudia Manriquez-Roman, Elizabeth L. Siegler, Justyna J. Gleba, Truc N Huynh, Grace DeFranco, Aylin Alasonyalilar Demirer, Matthew L. Pawlush, Michael Redig, Skyeler Klinge, Long K, James L. Miller, Erin Miller, Brooke Kimball, Erin E. Tapper, R. Leo Sakemura, Carli M. Stewart, İsmail Can, Olivia Sirpilla, Jennifer M. Feigin, Kun Yun, Omar L. Gutierrez-Ruiz, Hong Xia, M. Hefazi, Kendall J. Schick, Ekene J. Ogbodo, Gloria Olivier, Yushi Qiu, Robert C. Smallridge, Abba Zubair, H. Tun, Copland John A., Saad S. Kenderian
Antigen loss remains a major barrier to chimeric antigen receptor (CAR) T cell efficacy in solid tumors. In aggressive thyroid cancers, dedifferentiation is accompanied by coordinated loss of lineage-restricted surface antigens, limiting immune recognition. Thyroid-stimulating hormone receptor (TSHR) expression was assessed on multiple histotypes of thyroid cancer via immunohistochemistry. TSHR-directed chimeric antigen receptor T (CART) cell therapy was assessed against differentiated thyroid cancer subtypes which highly expressed TSHR and dedifferentiated thyroid cancer subtypes which downregulated TSHR in vitro and in xenograft and patient-derived xenograft (PDX) mouse models. MAPK inhibitors were assessed in combination with TSHR-CART cell therapy in dedifferentiated thyroid cancers which downregulated TSHR in vitro and in PDX mouse models. Using TSHR as a clinically relevant antigen target, we demonstrated that pharmacologic tumor redifferentiation can restore target expression and sensitize tumors to CART cell therapy. TSHR-CART cells mediate durable antigen-specific cytotoxicity in TSHRhigh differentiated thyroid cancer models but are limited in TSHRlow dedifferentiated tumors. In patient-derived anaplastic thyroid cancer xenografts, MAPK inhibition restores TSHR expression and converts tumors from CAR-resistant to CAR-responsive. Concurrent redifferentiation therapy and CART cell treatment yields superior tumor control and survival versus monotherapy, without impairing CART cell function. These findings establish tumor redifferentiation as a generalizable strategy to overcome antigen loss and enhance CART cell therapy in thyroid cancer and potentially other solid tumors.