Altered Thymopoiesis in Thymoma Is Associated with Defects in Negative Selection Machinery and Decreased Treg Abundance

Thymomas are rare thymic epithelial tumors harboring a high but variable proportion of lymphocytes without obvious function. Autoimmunity is present in one third of patients at diagnosis. In this study, we performed a phenotypic, single-cell RNA sequencing and spatial analysis of both the T cells and tumoral cells. T cells at all stages of T-cell development-from immature to mature-were present in the tumor, suggesting active thymopoiesis in thymoma. However, data generated through multiple approaches suggested a maturation blockade at the double-negative to double-positive stage of T-cell development. In the mature T-cell compartment, the frequency of regulatory T cells was strongly decreased. The single-cell RNA sequencing analysis showed that the transcriptome of tumoral thymic epithelial cells (TEC) was most similar to that of nontumoral medullary TEC, but the expression of key molecules involved in positive and negative selection was defective. Multiplexed IHC consecutive staining revealed a loss of the cortex-medulla zoning in thymoma, which may be related to a decrease in the expression of T cell-targeted chemokines by tumoral TEC. Altogether, these results suggest that the thymopoiesis present in thymoma is abnormal and may be the cause of the prevalent autoimmunity observed in this disease.

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Journal
Cancer Immunology Research
Published
2025-10-27
DOI
https://doi.org/10.1158/2326-6066.cir-25-0190
Primary Topic
Neurobiology and Insect Physiology Research
Type
article
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article

Altered Thymopoiesis in Thymoma Is Associated with Defects in Negative Selection Machinery and Decreased Treg Abundance

Konstantinos Zannis, Antoine Toubert, Eliane Piaggio, Yago A. Arribas et al.
Cancer Immunology Research
Neurobiology and Insect Physiology Research
article

Altered Thymopoiesis in Thymoma Is Associated with Defects in Negative Selection Machinery and Decreased Treg Abundance

Konstantinos Zannis, Antoine Toubert, Eliane Piaggio, Yago A. Arribas, Joshua J. Waterfall, Pierre‐Emmanuel Bonté, Sebastián Amigorena, Jan-Timon Werle, Rafael A. Paiva, Clémence Basse, Emmanuel Clave, Marine Lefèvre, Morgan Tourne, Jérémy Mesple, Marianne Burbage, Vahid Asnafi, Édouard Sage, Agathe Seguin‐Givelet, Christina Metoikidou, В. К. Карнаухов, Marion Salou, Olivier Lantz, Alessio Vincenzo Mariolo, Renaud Leclère, Aurélien Sutra Del Galy, Camille Kergaravat, Agata Cieślak, Coralie L. Guérin, I.D. Silva, Sylvain Baulande, Nicolas M Girard, Alexandre Lanau, Simon Lefranc, Marine Roxane. Largeau
article en

Abstract

Thymomas are rare thymic epithelial tumors harboring a high but variable proportion of lymphocytes without obvious function. Autoimmunity is present in one third of patients at diagnosis. In this study, we performed a phenotypic, single-cell RNA sequencing and spatial analysis of both the T cells and tumoral cells. T cells at all stages of T-cell development-from immature to mature-were present in the tumor, suggesting active thymopoiesis in thymoma. However, data generated through multiple approaches suggested a maturation blockade at the double-negative to double-positive stage of T-cell development. In the mature T-cell compartment, the frequency of regulatory T cells was strongly decreased. The single-cell RNA sequencing analysis showed that the transcriptome of tumoral thymic epithelial cells (TEC) was most similar to that of nontumoral medullary TEC, but the expression of key molecules involved in positive and negative selection was defective. Multiplexed IHC consecutive staining revealed a loss of the cortex-medulla zoning in thymoma, which may be related to a decrease in the expression of T cell-targeted chemokines by tumoral TEC. Altogether, these results suggest that the thymopoiesis present in thymoma is abnormal and may be the cause of the prevalent autoimmunity observed in this disease.

Cancer Immunology ResearchVol. 14(1)
Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Versailles Saint-Quentin-en-Yvelines (FR), Université Paris Cité (FR), Université Paris Sciences et Lettres (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), The Netherlands Cancer Institute (NL), Microbiologie de l’alimentation au service de la santé (FR), Institut Necker Enfants Malades (FR), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Sorbonne Paris Cité (FR), Institute Mutualiste Montsouris (FR), Assistance Publique – Hôpitaux de Paris (FR), Hospices Civils de Lyon (FR), Immunité et Cancer (FR), Virologie et Immunologie Moléculaires (FR), Hôpital Saint-Louis (FR), Clinique Hartmann (FR), Hôpital Foch (FR), Institut Curie (FR)
Openalex Percentile: Top 66%
Neurobiology and Insect Physiology Research
DOISourceOpenAlex
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