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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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Redifferentiation-enabled TSHRCART cells overcome antigen loss in aggressive thyroid cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Claudia Manriquez-Roman,
  • Elizabeth L. Siegler,
  • Justyna J. Gleba,
  • Truc N. Huynh,
  • Grace E. DeFranco,
  • Aylin Alasonyalilar Demirer,
  • Matthew L. Pawlush,
  • Michael Redig,
  • Skyeler M. Klinge,
  • Long K. Mai,
  • James L. Miller,
  • Erin E. Miller,
  • Brooke L. Kimball,
  • Erin E. Tapper,
  • R. Leo Sakemura,
  • Carli M. Stewart,
  • Ismail Can,
  • Olivia L. Sirpilla,
  • Jennifer M. Feigin,
  • Kun Yun,
  • Omar L. Gutierrez-Ruiz,
  • Hong Xia,
  • Mehrdad Hefazi,
  • Kendall J. Schick,
  • Ekene J. Ogbodo,
  • Gloria Olivier,
  • Yushi Qiu,
  • Robert C. Smallridge,
  • Abba Zubair,
  • Han W. Tun,
  • John A. Copland,
  • Saad S. Kenderian

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.