The potential role of the thymus in immunotherapies for acute myeloid leukemia

Abstract

Understanding the factors which shape T-lymphocyte immunity is critical for the development and application of future immunotherapeutic strategies in treating hematological malignancies. The thymus, a specialized central lymphoid organ, plays important roles in generating a diverse T lymphocyte repertoire during the infantile and juvenile stages of humans. However, age-associated thymic involution and diseases or treatment associated injury result in a decline in its continuous role in the maintenance of T cell-mediated anti-tumor/virus immunity. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that mainly affects older adults, and the disease's progression is known to consist of an impaired immune surveillance including a reduction in naïve T cell output, a restriction in T cell receptor repertoire, and an increase in frequencies of regulatory T cells. As one of the most successful immunotherapies thus far developed for malignancy, T-cell-based adoptive cell therapies could be essential for the development of a durable effective treatment to eliminate residue leukemic cells (blasts) and prevent AML relapse. Thus, a detailed cellular and molecular landscape of how the adult thymus functions within the context of the AML microenvironment will provide new insights into both the immune-related pathogenesis and the regeneration of a functional immune system against leukemia in AML patients. Herein, we review the available evidence supporting the potential correlation between thymic dysfunction and T-lymphocyte impairment with the ontogeny of AML (II-VI). We then discuss how the thymus could impact current and future therapeutic approaches in AML (VII). Finally, we review various strategies to rejuvenate thymic function to improve the precision and efficacy of cancer immunotherapy (VIII).

Keywords: AML-acute myeloid leukemia; T lymphocytes; aging; hematopoietic (stem) cell transplant (HCST); immunosenescence; immunotherapy; thymus; tumor microenvironment.

Figure 1

Historical timeline of major discoveries on the thymus and the development of FDA approved cancer immunotherapies. Major breakthroughs in understanding the functional role of the thymus began in the late 1950s to early 1960s. These landmark discoveries paved the way for breakthroughs in T cell biology and eventually ushered in a new era for cancer immunotherapy. Elements of this figure were generated using Biorender.com.

Figure 2

Schematic illustration of intrathymic T cell development and current approaches to thymus rejuvenation. T cell development begins with migration of hematopoietic stem cells (HSC) from the bone marrow to the thymus. These thymic seeding progenitors (TSPs) undergo lineage commitment as they transform from double negative (DN) to double positive (DP) to single positive T cells with the assistance from critical signals within the thymic epithelial microenvironment. T cells are eventually exported out of the thymus as CD4+, CD8+ or regulatory T cells (Tregs) where they function within the periphery. Various therapeutic approaches (in red) to rejuvenating thymic function are currently under investigation. This includes approaches to 1) target hematopoietic progenitors and thymocytes, 2) target the thymic epithelial microenvironment, 3) modulate hormones and metabolism, and 4) develop cellular therapies to replace thymic tissue. Elements of this figure were generated using Biorender.com.

Figure 3

Schematic illustration summarizing the crosstalk between the bone marrow and thymic microenvironment, and its influence on the AML TME. Hematopoietic stem cells derived from the leukemic bone marrow microenvironment can travel to the thymus where they differentiate into T cells. The resulting T cells are then exported to the periphery, where they may then recirculate back into the bone marrow as tumor infiltrating lymphocytes. Environmental insults such as aging, cytoreductive therapy, HSCT pre-conditioning, and FLT3 inhibition may impair thymopoiesis and subsequently promote tumor immune evasion through immunosenscence. The immunosuppressive bone marrow microenvironment can also independently impair thymic function through MCP-1/CCl2 expression and reduction in thymic seeding progenitors. Elements of this figure were generated using Biorender.com.