Immune aberrations in thymic epithelial tumors

Introduction

Thymomas, thymic carcinomas (TCs), and thymic neuroendocrine tumors, collectively known as thymic epithelial tumors (TETs), are rare cancers that arise from cortical or medullary thymic epithelial cells (TECs) (1). The histological classification of TETs as defined by the World Health Organization (WHO) takes into account the morphological and immunohistochemical features of tumor cells and the proportion of immature T cells in the tumor (2). TETs are characterized by a low tumor mutation burden (TMB) and a paucity of actionable genomic changes, which create obstacles to the development of targeted biologic therapies for these diseases (3). A propensity towards paraneoplastic autoimmunity adds to the challenges of drug development for TETs by limiting the use of immunotherapies to a subset of patients with TC with no clinical history of autoimmune disease or use of immunosuppressants (4).

Surgical resection is the cornerstone of management for patients with potentially resectable disease, whereas definitive systemic therapy is used for the management of unresectable TETs or for the treatment of inoperable recurrent disease (5). Unfortunately, the risk of disease recurrence after front-line therapy is not insubstantial for patients with locally-advanced or metastatic TETs, with recurrence rates in excess of 50% for patients with pleural or pericardial involvement, or with metastatic disease at diagnosis (6). Systemic therapy in this setting is generally characterized by low response rates and a limited duration of benefit due to the emergence of acquired resistance to treatment (5). Immune checkpoint inhibitors (ICIs) provide a sliver of hope in this setting since a subset of patients with TC experience durable clinical responses, which has a positive impact on survival, albeit with an increased risk of developing immune-mediated toxicity (7).

Several efforts are underway to identify biomarkers of response and toxicity to immunotherapy in patients with TETs in an effort to broaden the use of these revolutionary treatments across histological subtypes and clinical contexts (8,9). However, limited data are available to date on the immunological profile of TETs, with existing literature largely focusing on tumor cell expression of markers such as programmed cell death-ligand 1 (PD-L1), and TMB (10). This review describes ongoing attempts to gain fundamental insights into immune aberrations in TETs, including efforts to understand the immune cell composition and the tumor microenvironment (TME) of these rare cancers.

Thymic structure and T cell development

An interpretation of the immune profile of TETs requires an understanding of thymic structure and its role in T cell development since immature T cells constitute an integral part of several histological subtypes of thymomas.

The thymus plays a crucial role in T cell development, which commences with the entry of T cell precursors from the bone marrow into the thymus at the corticomedullary junction. The stages of T cell development in the thymus are typically distinguished by changes in the expression of the surface co-receptor molecules CD4 and CD8 that progress from double-negative (DN) to double-positive (DP) expression on developing T cells (11). DN thymocytes represent the early stages of development of progenitor cells committed to the T cell lineage. Rearrangement of genes of the T cell receptor (TCR) locus leads to the generation of a γδ TCR or an αβ TCR. The γδ TCR rearrangement is completed at the DN developmental stage and results in the formation of mature γδ T cells. αβ T cells develop from T cell precursors that rearrange the TCRβ chain and subsequently undergo upregulation of CD4 and CD8 co-receptors leading to the generation of DP thymocytes. This is followed by TCRα rearrangement and expression of an αβTCR at the cell surface. DP cells interact with self-antigens in the context of major histocompatibility complex (MHC) class I or class II molecules. Cells that engage antigen/MHC with an appropriate affinity survive and migrate into the medulla by upregulating expression of CCR4 and CCR7 (12). In the thymic medulla T cell precursors undergo negative selection in the presence of tissue self-antigens on antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages. Self-reactive thymocytes undergo apoptosis leading to the establishment of central tolerance or are diverted into the immunosuppressive regulatory T cell (Treg) lineage. The expression of tissue self-antigens is controlled by the transcription factors AIRE and Fezf2 (13,14). DP thymocytes that recognize MHC-I commit to the cytotoxic lineage via the CD8 locus and develop into CD8⁺ single-positive (SP) thymocytes, whereas those that recognize MHC-II commit to the helper lineage via the CD4 locus and develop into CD4⁺ SP thymocytes. Recent research has shown the existence of intermediate developmental stages where the strength of the TCR signal influences coreceptor gene activity and the ultimate determination of CD4 or CD8 T cell lineage (15). Mature naïve T cells develop migration competence and enter secondary lymphoid organs (spleen and lymph nodes) through a complex process that involves upregulation of the transcription factor KLF2 in late-stage thymocytes and expression of L-selectin, which facilitates interaction with endothelial venules and homing to lymph nodes (16). A specialized subset of γδ T cells derived from DN thymocytes known as “peacekeepers of the immune system” produce interferon (IFN)-γ and interleukin (IL)-17 and play a unique role in maintaining lymphoid, metabolic and tissue homeostasis (17).

Effect of tumor composition on immune profile

Solid tumors are composed of a complex TME that is broadly composed of tumor cells, stroma and immune cells (18). Immune aberrations associated with cancer derive from interactions of tumor cells with stromal components such as fibroblasts, blood vessels and the extracellular matrix (ECM), and from the genomic characteristics of tumors cells themselves (18,19). Cancer-associated fibroblasts (CAFs) and endothelial cells alter the TME by recruiting immunosuppressive myeloid cells and proangiogenic factors, respectively (19). CAFs can be broadly classified into tumor-promoting and tumor-suppressive CAFs. With the growing recognition of the importance of these cells in tumor biology, CAFs are being explored as potential biomarkers and targets for prevention and treatment of cancers (19).

Finally, genetic mutations play a vital role in modulation of the TME and in shaping the immune profile of tumors. For example, certain mutations produce neoepitopes on tumor cells which are recognized by immune effector cells and are associated with increased T cell infiltration into the TME, whereas other mutations can alter molecular pathways that ultimately drive the recruitment of immunosuppressive cells into the TME (18).

These observations demonstrate the effects of a variety of tumor-intrinsic and tumor-extrinsic factors on the immune composition of tumors including the relative proportions of immune cell subsets, such as T and B lymphocytes, natural killer (NK) cells, DCs, macrophages, and myeloid derived suppressor cells (MDSCs). In turn, immune cells exert variable effects on tumor kinetics and the TME that depend on their interactions with other cell types (18). Cytotoxic CD8 T lymphocytes recognize tumor cells in an antigen-specific manner when primed by DCs, primarily in secondary lymphoid organs, but also within tumor tissue or within organized tertiary lymphoid organs. In case of loss of MHC-I molecules on tumor cells, a common mechanism of immune evasion, cytotoxic NK cells can also exert anti-tumor killing independent of any previous interaction with APCs. Other immune cells, such as tumor-promoting M2 macrophages and immature granulocytic and monocytic MDSCs can contribute to tumor progression through the induction of stromal cell proliferation, vascularization, ECM deposition and cell migration. Tregs are immunosuppressive and exert their effect through immunosuppressive factors, such as IL-10 and adenosine, and through modulation of APC function (18). Attempts have been made to correlate the immunological profile and clinical behavior of tumors by developing an “immunoscore” with prognostic implications. Studies in melanoma, ovarian cancer and colorectal cancer have demonstrated an association between the degree of tumor infiltration by CD8 T cells and T-helper 1 (Th1) cells, and clinical outcomes (20).

Immune aberrations in TETs

With this background, we now shift our focus to recent data describing immune aberrations in TETs. Although the presence of a hematopoietic compartment consisting of immature thymocytes makes it difficult to distinguish between infiltrating immune cells in the TME and the physiological constituents of these unique tumors, efforts are underway to describe the immune profile of TETs using tumor tissue and peripheral blood derived from patients with thymic cancers.

T cell profile

A recent study of the cellular composition of TETs used surgically resected samples from 42 patients (Masaoka stage I–II =29) who had not received chemotherapy previously. Twenty-five samples were analyzed using multi-platform analysis that included hematoxylin and eosin (H&E) and immunofluorescence evaluation, mass cytometry, single-cell RNA sequencing (scRNAseq) and TCR profiling (21). CD45⁺ immune cells constituted the dominant cell type in these samples, with varying proportions of immune cells in different WHO histological subtypes. Type A-B2 thymomas had a greater proportion of CD4⁺CD8⁺ T cells compared with TCs, whereas type A and AB thymomas had a lower proportion of B cells compared with type B thymomas and TCs. The T cell profile also varied across histological subtype and stage of TETs with DP T cells representing the largest fraction of T cells in thymomas and in early-stage disease compared with TCs and advanced stage disease. TCs were characterized by a larger proportion of immunosuppressive regulatory T cells compared with other histological subtypes and normal thymus.

Programmed cell death protein-1 (PD-1) expression on intratumoral T cells was evaluated in 31 resection samples from patients with predominantly early-stage thymomas (Masaoka stage I–II =27). CD4 and CD8 SP T lymphocytes expressed PD-1 at significantly higher rates in type AB, B1 and B2 thymomas compared with type A and B3 thymomas (22). T cell receptor excision circles (TRECs), which are detected in newly formed naïve T cells in the thymus, were also detected in higher amounts in CD4 and CD8 T cells from type AB, B1 and B2 thymomas compared with type A and B3 thymomas. These findings could explain, in part, the clinical observations of a high frequency of immune-mediated toxicity in association with PD-1-directed ICIs in patients with lymphocyte-rich thymomas (23).

The immune cell composition of advanced thymomas is less well studied. In a phase I clinical trial of the anti-PD-L1 antibody, avelumab that included seven patients with metastatic thymoma, analysis of a pre-treatment biopsy from a patient with previously treated WHO type B1 thymoma showed a large proportion of CD4⁺ T cells and smaller proportions of macrophages in different stages of differentiation. The biopsy also contained scant B cells and a notable absence of forkhead box P3 (FoxP3)+ regulatory T cells (24).

Human leukocyte antigen (HLA) expression

The MHC, also known as the HLA complex in humans, is located on chromosome 6 (6p21.3). MHC class II is expressed in TECs and plays a role in T cell maturation (25). Downregulation or loss of MHC-II expression on tumor cells is a known mechanism of cancer immune evasion. Loss of heterozygosity (LOH) is the most common mechanism of HLA haplotype absence in a malignant tumor, and the frequency of LOH-6p21 has been reported in many cancer types. One of the most frequent genomic aberrations in thymomas is the loss of chromosome 6, including the MHC locus, 6p21.31 (26). In a study of genetic aberrations of thymomas, deletions involving chromosome 6 have been reported to alter immunological properties of thymomas and postulated to have a role in the pathogenesis of paraneoplastic autoimmunity characteristic of thymoma (27). Another study of MHC expression in TECs showed decreased MHC-II expression on neoplastic TECs (28). The expression level of MHC-II was also directly proportionate to the mature CD3⁺ cells in the CD4⁺CD8⁻ subset, and hence increased CD3⁻CD4⁺CD8⁻ cells in thymoma may result from impaired expression of MHC class II molecules and expression of HLA-DR.

HLA expression in previously treated TETs and changes in expression in response to treatment need further evaluation. Immune correlative studies from the previously mentioned study of avelumab in metastatic thymoma showed low and heterogenous expression of HLA class II in pre- and post-treatment biopsies from a patient with previously treated WHO type B1 thymoma, and increased expression of HLA-I in post-treatment tumor biopsies (24).

The TET TME

Surgically resected tumor samples from 21 patients (thymoma =15, TC =6; Masaoka stage I–II =53%, stage III–IV =47%) were analyzed by RNA sequencing and whole exome sequencing (WES) to evaluate the TET TME (29). An immune score was calculated by comparing immune cells to stromal cells. Type A thymoma and TC were found to have lower scores than other subtypes. Higher immune cell infiltration with both effector (CD8 T cells, DC, Th1) and tumor suppressor (MDSC) cells was noted in thymoma compared with TC, whereas TC had a significantly higher stromal score. Of note, several studies have demonstrated an association between higher immune/stromal scores and improved prognosis for various types of tumors, including hepatocellular carcinoma, pancreatic cancer, melanoma, and lung cancer (30). Gene expression analysis of cytokines involved in the immune response was also performed, including evaluation of the proinflammatory gene, high mobility group box 1 (HMGB1). HMGB1 is a multifunctional molecule with pleiotropic effects in cancer. Extracellular-HMGB1 is important for the immunogenic cell death of cancer cells and stimulates an antitumor immune response during chemotherapy by stimulating T cells, recruiting inflammatory cells and mediating interactions between NK cells, DCs, and macrophages (31). HMGB1-related genes showed higher expression in type A, B1, and B2 thymomas compared with TCs. Lower expression of HMGB1 was associated with worse survival. CD40 ligand, involved in activation of the innate and adaptive immune systems (32), was expressed in type B thymomas versus type A thymoma and TC. Genes associated with transforming growth factor-β1, a pleiotropic cytokine, which can promote tumor progression in late-stage cancers (33), showed a non-statistically significant increase in expression in TC compared with thymomas.

Other studies have shown differences in the proportion of immune cells constituting the tumor immune microenvironment (TIME) in resected TETs based on tumor histology (34). These differences are broadly outlined in Table 1.

Taken together, these results highlight the complexity of the TET TME and its potential influence on clinical outcomes.

TCR diversity

T cells display a diverse TCR repertoire arising from the T cell maturation process in the thymus. The ability to generate a robust adaptive immune response is linked to increased TCR diversity (35). TCR analysis by RNA sequencing of surgically resected TETs showed significantly higher T cell diversity in type B2 and B3 thymomas compared with TC (P<0.05) (29). Interestingly, an increase in baseline TCR diversity in peripheral blood mononuclear cells from patients with advanced thymoma receiving immunotherapy, is associated with a higher likelihood of developing an anti-tumor response and an increased risk of immune-mediated adverse events (24).

Other immune markers

PD-L1 expression, TMB and microsatellite status are among the most widely studied biomarkers of response to ICIs (36). However, the utility of these biomarkers for TETs is limited for a variety of reasons. Although trials of ICI monotherapy have demonstrated an association between tumor cell PD-L1 expression and anti-tumor activity (23,37), the clinical relevance of PD-L1 expression as a predictive biomarker of response to immunotherapy across TET histologies is debatable. Previous studies have shown high PD-L1 expression in non-neoplastic TECs with medullary tropism around Hassall’s corpuscles (38). Constitutive expression of PD-L1 in thymic tissue might explain the wide range of expression values observed in TETs and call into question its value as a predictive biomarker for immunotherapy, especially for thymomas (39). On the other hand, TMB and microsatellite status likely retain their predictive value for ICIs in TETs but are seldom relevant for clinical management due to the low TMB and rarity of microsatellite instability in TETs (40). Despite these limitations, expression of immune markers such as indoleamine 2,3-dioxygenase and FoxP3 in Tregs has been shown to vary among TETs and appears to have prognostic value in TC (41).

The peripheral immunome

Interrogation of the peripheral immunome can offer important prognostic insights and potentially facilitate the identification of predictive biomarkers for systemic therapy. In a retrospective study of 71 cases of completely resected, predominantly early-stage TETs, including 64 thymomas and 6 TCs, a significant correlation was observed between high pre-treatment leucocyte, neutrophil and platelet counts, and worse relapse-free survival (42). A high neutrophil-to-lymphocyte ratio (NLR) has also been reported as a poor prognostic indicator in several malignancies (43). Multiple studies have shown an association between high preoperative NLR in patients with completely resected thymomas and worse clinical outcomes (44,45). In the context of immunotherapy, early data from patients with thymoma receiving an ICI appear to show a higher likelihood of response in patients with a higher baseline absolute lymphocyte count, and lower frequencies of B cells, Tregs, conventional DCs and NK cells (24). Pre-treatment B cell lymphopenia and lower frequencies of CD4⁺ T cells, NK cells, and Tregs have been observed in patients who developed immune myositis (46). Although these preliminary data from a small cohort of patients should be considered trends, these observations highlight the potential for identification of predictive biomarkers by conducting comprehensive immunological profiling of the peripheral immunome in patients with TETs to identify pre-existing immune aberrations and correlating these with clinical outcomes.

AIRE expression and paraneoplastic autoimmunity

Based on the established roles of AIRE and Fezf2 in medullary presentation of tissue-restricted antigens, reduced AIRE and Fezf2 expression in the majority of thymomas impairs central tolerance by limiting antigen display to developing thymocytes (14,47). This, in turn, permits escape of autoreactive T cells and increases the susceptibility to paraneoplastic autoimmunity and immune-mediated toxicity. Loss of AIRE expression in thymomas also explains, in part, the greater propensity towards autoimmune disease associated with these tumors when compared with TCs (48). Prospective evaluation of AIRE/Fezf2 expression across TET subtypes and clinical correlation with paraneoplastic autoimmune syndromes and immune-mediated toxicity is required to validate these findings.

Conclusions

Several efforts are underway to study the immunological profile of TETs with a goal of improving our current understanding of TET immune composition and the TIME. Recently reported results show variations in the immune cell profile of TETs and the composition of the TET TIME by histology and stage. These results have largely been derived from analyses of surgical resection samples from patients with early-stage TETs who have not received cytotoxic chemotherapy. Limited information is available on the immune composition of advanced TETs. The effects of systemic therapy on TET immune profile and variations arising at metastatic sites compared with the primary tumor represent gaps in knowledge that, if addressed, could yield important clinical insights. Interactions between the epithelial and hematological compartments of TETs and the impact of the stroma on tumor immune profile also need further investigation.

Major obstacles in drug development for TETs include a paucity of actionable targets, both genomic and immunologic, and an increased risk of autoimmunity. A comprehensive evaluation of TET immunology has the potential to address some of these challenges and provide valuable information to facilitate the development of immunotherapeutics and improve clinical outcomes for patients with these rare cancers.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Malgorzata Szolkowska) for “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-25-30/prf

Funding: This research was supported (in part) by the Intramural Research Program of the National Institutes of Health (NIH) (No. ZID BC 011543). The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-25-30/coif). “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” was commissioned by the editorial office without any funding or sponsorship. A.R. reports research funding to his institution from Promontory Therapeutics. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Copyright Information: The authors of this manuscript are U.S. Government employees. Since this manuscript has been prepared within the scope of their employment, it should be considered to be in the public domain in the USA and not require a transfer or license of rights.

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