The theragnostic advances of exosomes in managing leukaemia

Abstract

Leukaemia, a group of haematological malignancies, presents ongoing diagnosis, prognosis, and treatment challenges. A major obstacle in treating this disease is the development of drug resistance. Overcoming drug resistance poses a significant barrier to effective leukaemia treatment. The emergence of exosome research has unveiled new insights into the probable theragnostic implementations in leukaemia. Various research has exhibited the diagnostic possibilities of exosomes in identifying leukaemia-specific biomarkers, including genetic mutations and fusion transcripts. Additionally, exosomes have been implicated in disease progression and treatment response, rendering them appealing targets for therapeutics. Exosomes, originating from diverse cell types, are instrumental in intercellular communication as they participate in the functional transportation of molecules like proteins, nucleic acids and lipids across space. Exosomes have a dual role in immune regulation, mediating immune suppression and modulating anti-leukaemia immune responses. Interestingly, exosomes can even act as drug transport vehicles. This review delves into the intricate process of exosome biogenesis, shedding light on their formation and release from donor cells. The key mechanisms engaged in exosome biogenesis, for instance, the endosomal sorting complexes required for transport (ESCRT) machinery and ESCRT-independent pathways, are thoroughly discussed. Looking ahead, future approaches that leverage innovative technologies hold the promise of revolutionizing disease management and improving patient outcomes.

Keywords: biogenesis; drug resistance; exosomes; leukaemia; therapeutics.

FIGURE 1

Exosome Biogenesis (Adapted with permission from ref Copyright© 2022 American Chemical Society).

FIGURE 2

The impact of exosomes derived from immune cells on the cellular components of the immune system is noteworthy. These exosomes originate from various immune cells such as B‐lymphocytes (B cells), T‐lymphocytes (including CD4+, CD8+ and Treg subsets), Natural Killer cells (NK‐cells), Dendritic cells, other antigen‐presenting cells (APCs) and Myeloid‐Derived Suppressor Cells (MDSC). Immune cell‐derived exosomes can influence various other cells involved in immune responses. Exosomes can stimulate the immune response by presenting peptide–MHC complexes to T cells, transferring antigens to other dendritic cells, and activating T cells, B cells and NK cells. Likewise, exosomes from Treg and NK cells exhibit inhibitory functions, which include suppressing the adaptive arm of the immune response and inducing the destruction of tumour cells by NK cells. Exosomes derived from MDSC also play a significant role in immune suppression, primarily by activating Treg and promoting a Type‐2 Tumour promoting phenotype in macrophages (T‐2 TP macrophages) (Adapted with permission from ref. Copyright © 2022, The Author(s)).

FIGURE 3

Metastasis in the Bone Marrow (BM). Chemokine stromal cell‐derived factor 1 (SDF1) regulates the homing of the cells. Integrin, VLA‐4 and e‐Selectin assist it. In the sinusoidal niche, leukaemia cells develop and thrive under the influence of stromal cells, pericytes and colony‐stimulating factor 1 receptor‐positive (CSF1R+) monocytes. Leukaemia cells destroy haematopoietic stem cells and progenitor cells (HSPCs) by Stem cell factor (SCF). This hampers normal haematopoiesis and leads to the formation of a malignant niche. Leukaemia cells might also be the endosteal niche. Here, the oxygen‐limiting environment, osteopontin (OPN) and Transforming Growth Factor –β (TGF‐ β) enable the leukaemia cells to undergo a dormant state. This state resists chemotherapy. Granulocyte Colony Stimulating Factor(G‐CSF) aids in metastasis by animating the cancer cells. Enzymes like elastase and matrix‐metallo proteinase 2 and 9 (MMP2 and 9) may initiate extravasation. Natural Killer (NK) Cells might fight against the blood cancer cells in BM (Created in Biorender.com).

FIGURE. 4

Metastasis in the Spleen. Usually, metastasis occurs here as leukaemia becomes chronic. Growth of the white pulp is responsible for a hypertrophic phenotype exhibited by several individuals suffering from blood cancer. Entry of the Leukaemia cells through the sinusoidal vessels is regulated by CCL1‐CCR7 and Stromal Cell‐derived Factor‐1(SCF‐1)‐CXCR4. Ly6C+ leukaemia‐associated macrophages (LAMs) might aid leukaemia cells moving to the spleen by CCL8 and CCL9. Hyaluronan, monocyte‐derived nurse‐like cells, helper B cells and many other stromal factors aid the cancer cells in multiplying and thriving. (TGF‐ β: Transforming Growth Factor –β) (Created in Biorender.com).

FIGURE 5

The therapeutic utilization of exosomes encompasses various applications in clinical trials, including their role as biomarkers, cell‐free therapy (exosome therapy), carriers for drug delivery and cancer vaccines. Exosomes derived from plant cells, mesenchymal cells, T cells and dendritic cells are employed to treat diverse ailments. Furthermore, exosomes derived from these sources exhibit promise as vehicles for drug delivery systems. In the direct approach, therapeutic agents are loaded into exosomes. In contrast, the indirect methods involve genetic engineering or co‐culturing of specific cells with therapeutic agents to generate artificial exosomes (Adapted with permission from ref Copyright © 2022, The Author(s)).