Immunotherapy of thymic epithelial tumors: molecular understandings and clinical perspectives

Abstract

Immunotherapy has emerged to play a rapidly expanding role in the treatment of cancers. Currently, many clinical trials of therapeutic agents are on ongoing with majority of immune checkpoint inhibitors (ICIs) especially programmed death receptor 1 (PD-1) and its ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1, two main immune checkpoints, are expressed at high levels in thymic epithelial tumors (TETs) and could be predictors of the progression and immunotherapeutic efficacy of TETs. However, despite inspiring efficacy reported in clinical trials and clinical practice, significantly higher incidence of immune-related adverse events (irAEs) than other tumors bring challenges to the administration of ICIs in TETs. To develop safe and effective immunotherapeutic patterns in TETs, understanding the clinical properties of patients, the cellular and molecular mechanisms of immunotherapy and irAEs occurrence are crucial. In this review, the progress of both basic and clinical research on immune checkpoints in TETs, the evidence of therapeutic efficacy and irAEs based on PD-1 /PD-L1 inhibitors in TETs treatment are discussed. Additionally, we highlighted the possible mechanisms underlying irAEs, prevention and management strategies, the insufficiency of current research and some worthy research insights. High PD-1/PD-L1 expression in TETs provides a rationale for ICI use. Completed clinical trials have shown an encouraging efficacy of ICIs, despite the high rate of irAEs. A deeper mechanism understanding at molecular level how ICIs function in TETs and why irAEs occur will help maximize the immunotherapeutic efficacy while minimizing irAEs risks in TET treatment to improve patient prognosis.

Keywords: Immune checkpoint inhibitors; Immune-related adverse events; Immunotherapy; PD-1; PD-L1; Thymic epithelial tumors.

Fig. 1

Different forms of anticancer immunotherapy. A. ICIs, especially PD-1/PD-L1 inhibitors, are the main immunotherapies used in TET treatment and have accumulated the most evidence. B-E. Adoptive cell therapies, including CAR-T, TIL, TCR-T and NKC therapies, and different sources of therapeutic cells are obtained, modified or screened and expanded for infusion back into the patients. F. Therapeutic vaccines are designed based on discovered tumor neoantigens. The infused tumor vaccines induce an immune response to tumor cells and enhance antitumor immunity. G. Cytokines with immune activation functions, such as IL-2 and IFN-α/β, are recombined and synthesized in vitro and then infused into patients, which enhance the antitumor immune response. CAR: Chimeric antigen receptor; TIL: Tumor-infiltrating lymphocyte; TCR: T cell receptor; NKC: Natural killer cell

Fig. 2

Naïve T cell development in the normal thymus and thymoma. A. A healthy thymus with a normal structure and thymic microenvironment determines normal T cell development and maturation and continuously exports normal naïve T cells to establish normal immune function. B. Thymic epithelial tumors with distorted structures and disrupted microenvironments lack components that are necessary for positive and negative selection. Naïve T cells do not complete the central immune tolerance and emigrate to become autoreactive RTEs, which directly or indirectly lead to autoimmune diseases through the cellular or humoral immune systems, respectively. Pro T: Progenitor T cells; AChR: Acetylcholine receptor; AIRE: Autoimmune regulator effectors; RTEs: Recent thymic emigrants; DC: Dendritic cells; SLO: Secondary lymphoid organs

Fig. 3

PD-1/PD-L1 signaling in tumor immune tolerance. A. The mechanism of PD-1/PD-L1-mediated inhibition of T cell activation and PD-1/PD-L1 blocker-mediated T cell function restoration (between APCs and T cells). B. The mechanism of PD-1/PD-L1-mediated tumor immune tolerance and PD-1/PD-L1 blocker-mediated antitumor activity. Blockade of PD-1/PD-L1 alone and in combination with anti-TGF-β restores immune-exhausted T cells. CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; APC: Antigen-presenting cells; MHC: Major histocompatibility complex; TCR: T cell receptor; SHP2: Src homology 2 domain-containing tyrosine phosphatase 2

Fig. 4

An overview of irAEs in patients with TETs receiving PD-1/PD-L1 inhibitors. Immunotherapy is systemically administered to affect not only tumor progression but also the whole immune system, including central tolerance in the thymus and peripheral immune homeostasis. irAEs: Immune-related adverse events; TETs: Thymic epithelial tumors

Fig. 5

Some key issues requiring further mechanistic exploration. Comprehensive studies based on these issues will help researchers develop new biomarkers to prevent, monitor and manage irAEs during ICI therapy in patients with TETs. Autoimmune T cells and a disturbed TCR repertoire seem most relevant to irAEs, and a preclinical mouse model of irAEs is urgently needed to provide an ideal platform for mechanistic studies of irAEs. irAEs: Immune-related adverse events; ICIs: Immune checkpoint inhibitors; TETs: Thymic epithelial tumors

Fig. 6

Cellular and molecular mechanisms of immune imbalance in TETs immunotherapy. A. PD-1/PD-L1 interaction in the thymic tissue regulates T cell development, and antigen-activated T cells upregulate PD-1 to avoid overactivation mediated tissue attack. B. Activated T cells release IFN-γ which upregulate PD-L1 expression in tumor cells via ERK/JAK2-STAT signaling pathways. Additionally, some circRNAs expressed by tumor cells may be involved in regulation of immune imbalance in TETs. C. Some lncRNAs, LncXLOC_003810, for example, can inhibit PD-1/PD-L1signaling and may be involved in regulating T cell differentiation. PD-1/PD-L1 signaling can inhibit PI3K/AKT pathway, which, however, can be activated by some immune related miRNAs. D. The immune microenvironment in TETs is distorted. PD-1/PD-L1 and their directly or indirectly interacting molecules play a vital role in maintaining immune homeostasis either inside or outside the thymus. However, this balance is disrupted in TETs especially after immunotherapy, which make TETs susceptible to irAEs during immunotherapy. TCR: T cell receptor; SHP2: Src homology 2 domain-containing tyrosine phosphatase 2; irAEs: Immune-related adverse events; ICIs: Immune checkpoint inhibitors; TETs: Thymic epithelial tumors