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).

A Combination of the Immunotherapeutic Drug Anti-Programmed Death 1 with Lenalidomide Enhances Specific T Cell Immune Responses against Acute Myeloid Leukemia Cells

“…One of the first adoptive therapy clinical trials was performed on an AML patient (allogeneic transplantation) and led to a high rate of durable remissions in those who receive them. This demonstrates that leukemia could be eradicated by an effective immune response and the effectiveness of the immune response understandably plays an increasingly prominent role in treatment decisions in AML [36,37]. However, the role of checkpoint inhibitors, mainly those targeting T cells such as nivolumab and pembrolizumab or those targeting macrophages such as the anti-CD47 antibody magrolimab, are still under investigation.…”

Broadening the horizon: potential applications of CAR-T cells beyond current indications

“…The authors hypothesized a potential enhancement of patient’s endogenous anti-tumor capacities through elimination of tumor-antigen carrying APCs. Additionally, the thymus plays a central role in the development of the T-cell repertoire and could therefore be integral to the TME and success of immunotherapies for AML ( 156 ). Future research could investigate if the thymus is another possible focus of action to enhance the functionality of CAR-T-cell therapies.…”

Checkpoint Inhibitors in Acute Myeloid Leukemia

“…Athymic mice models exhibit peripheral neutropenia and BM immature granulocytic cell accumulation, an effect restored via a thymus graft or through the adoptive transfer of activated (but not naïve) CD4+ cells [ 16 , 17 ]. T helper polarization also contributes to normal hematopoiesis: in murine models, Th2-biased response induced a decrease in the number and cycling status of hematopoietic precursors, while the Th1-biased response shows an increased number of progenitors and cycling cells [ 18 ], suggesting the role of age-related thymus involution in AML pathogenesis [ 19 ]. As well as CD4+, activated CD8+ T-lymphocytes are involved in the regulation of the number of myeloid multipotent cells and committed precursors.…”