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

Sep 23, 2026

Uploaded by moss~

Background Antigen loss blocks the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors, and in aggressive thyroid cancers dedifferentiation brings coordinated loss of lineage-restricted surface antigens that restrict immune recognition. Methods TSHR expression was evaluated across thyroid cancer histotypes, then TSHR-directed CART cells were tested against differentiated and dedifferentiated subtypes in vitro and in xenograft/PDX mouse models. MAPK inhibition was assessed with TSHR-CART therapy in TSHR-downregulated cancers. Results Pharmacologic redifferentiation restored target expression and increased CART sensitivity, converting CAR-resistant to CAR-responsive tumors and improving control and survival without impairing CART function.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Introduction

Manriquez-Roman etal. Molecular Cancer (2026) 25:219 Molecular Cancer [https://doi.org/10.1186/s12943-026-02744-0](https://doi.org/10.1186/s12943-026-02744-0) RESEARCH Open Access Redifferentiation-enabled TSHRCART cells overcome antigen loss in aggressive thyroid cancers Claudia Manriquez-Roman1,2,3, Elizabeth L. Siegler2,3, Justyna J. Gleba4, Truc N. Huynh2,3, Grace E. DeFranco2,5,6, Aylin Alasonyalilar Demirer4, Matthew L. Pawlush4, Michael Redig4, Skyeler M. Klinge4, Long K. Mai2,3, James L. Miller4, Erin E. Miller4, Brooke L. Kimball2,3, Erin E. Tapper2,3, R. Leo Sakemura2,3, Carli M. Stewart2,6,7, Ismail Can2,3, Olivia L. Sirpilla2,3, Jennifer M. Feigin2,6,8, Kun Yun2,6,9, Omar L. Gutierrez-Ruiz2,3, Hong Xia2,3, Mehrdad Hefazi2,3, Kendall J. Schick2, Ekene J. Ogbodo2,3, Gloria Olivier10, Yushi Qiu4, Robert C. Smallridge 11, Abba Zubair12, Han W. Tun 13, John A. Copland4,8,9* and Saad S. Kenderian 1,2,3,5,6,9* Abstract 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 restoresTSHR 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. †Claudia Manriquez Roman, Elizabeth L. Siegler and Justyna J. Gleba contributed equally to this work. *Correspondence: John A. Copland [copland.john@mayo.edu](copland.john@mayo.edu)[ ](copland.john@mayo.edu)Saad S. Kenderian [Kenderian.saad@mayo.edu](Kenderian.saad@mayo.edu) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/

FAQs

Why does antigen loss limit CAR T cell therapy in aggressive thyroid cancers?

In aggressive thyroid cancers, dedifferentiation causes coordinated loss of lineage-restricted surface antigens, reducing immune recognition and limiting CART cell efficacy.

How was TSHR expression and therapy response evaluated?

TSHR expression was measured across multiple thyroid cancer histotypes using immunohistochemistry, and TSHR-directed CART cells were tested in vitro and in xenograft and patient-derived xenograft (PDX) mouse models.

What role does redifferentiation play in improving CART cell responses?

Pharmacologic tumor redifferentiation restores TSHR target expression, sensitizes tumors to CART cell therapy, and—when combined concurrently—improves tumor control and survival compared with monotherapy.

Sep 23, 2026

Uploaded by moss~