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ResearchIn-Press PreviewEndocrinologyImmunology Open Access | 10.1172/JCI191781

Loss of tumor cell MHC Class II drives MAPK-inhibitor insensitivity of BRAF-mutant anaplastic thyroid cancers

Vera Tiedje,1 Jillian Greenberg,1 Tianyue Qin,1 Soo-Yeon Im,1 Gnana P. Krishnamoorthy,1 Laura Boucai,2 Bin Xu,3 Jena D. French,4 Eric J. Sherman,2 Alan L. Ho,2 Elisa de Stanchina,5 Nicholas D. Socci,6 Jian Jin,7 Ronald A. Ghossein,3 Jeffrey A. Knauf,1 Richard P. Koche,8 and James A. Fagin1

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Im, S. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Xu, B. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Ho, A. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by de Stanchina, E. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Socci, N. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Jin, J. in: PubMed | Google Scholar |

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Ghossein, R. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Knauf, J. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Koche, R. in: PubMed | Google Scholar

1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Denver, Aurora, United States of America

5Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacologic, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States of America

8Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States of America

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Published August 19, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI191781.
Copyright © 2025, Tiedje et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 19, 2025 - Version history
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Abstract

Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse BrafV600E-driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita–/– and H2-Ab1–/– ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.

Supplemental material

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Version history
  • Version 1 (August 19, 2025): In-Press Preview
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