Laercio DaSilva1, Marieke Lavaert2, Alisa K. Sivapiromrat1, Shannon Swift1, Meredith J. McAdams1, Chen Zhao1, Arun Rajan1,3, Avinash Bhandoola2
1Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;
2Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;
3Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Correspondence to: Arun Rajan, MD. Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10-CRC, Room 4-5330, Bethesda, MD 20892, USA; Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Email: rajana@mail.nih.gov; Avinash Bhandoola, MB, BS, PhD. Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 1108, Bethesda, MD 20892-4254, USA. Email: avinash.bhandoola@nih.gov.
Background: Thymic epithelial cells (TECs) play a crucial role in T cell development and can be classified as cortical (cTEC) or medullary (mTEC). While cTECs support the expansion of T-lineage committed progenitors, mTECs are responsible for development of immunological self-tolerance. Thymic epithelial tumors (TETs) disrupt T cell development, predisposing patients to autoimmune disease (AD), which lowers their quality of life and limits treatment options. Herein, we conducted multimodal analyses of tumor-T cell interactions to dissect the immune microenvironment in TETs and explore its role in tumorigenesis and TET-related AD.
Methods: We applied the AutoGeneS algorithm to predict the frequency of various cell types within bulk TET samples using gene signatures from the Human Cell Atlas. Subsequently, we performed scRNAseq on a type AB thymoma from a patient with AD. We integrated these data into the Human Thymus Atlas to identify distinct cell populations. We used the CellphoneDB algorithm to detect signaling pathways linked to tumor growth. Tissue samples were derived from patients enrolled in a National Institutes of Health Institutional Review Board (NIH IRB)-approved clinical trial (NCT02146170).
Results: Preliminary analysis predicted high proportions of developing double positive (DP) thymocytes within AB, B1, and B2 thymomas, consistent with the World Health Organization (WHO) classification. Analysis of the epithelial and stromal compartments revealed that thymomas and thymic carcinomas consisted predominantly of cTECs and mTECs, respectively. scRNAseq of an AB thymoma identified developing thymocytes, infiltrating macrophages, and malignant TECs. The epithelial compartment consisted exclusively of cTECs. Comparison of cells from TETs with normal datasets unveiled diminished signaling between DPs and heightened signaling between immature single-positive precursors (ISPs) and tumor cells.
Conclusions: An imbalance of TEC subtypes is highly suggestive of aberrant thymic function resulting from distinct ontologies between TET subtypes, which enables autoreactive T cells to develop, resulting in AD. Detection of active thymopoiesis in an AB thymoma provides a potential explanation for an ongoing risk of AD during the course of the disease. Malignant cTECs interact differently with their microenvironment compared with non-malignant cTECs. These findings highlight the importance of a deeper study of tumor-T cell interactions for potential clinical innovations.
Keywords: Thymic tumor; T-cell development; cortical thymic epithelial cell (cTEC); medullary thymic epithelial cell (mTEC); autoimmunity
