The protective role of the microenvironment in hairy cell leukemia treatment: Facts and perspectives

Abstract

Hairy cell leukemia (HCL) is an incurable, rare lymphoproliferative hematological malignancy of mature B cAlthough first line therapy with purine analogues leads to positive results, almost half of HCL patients relapse after 5-10 years, and standard treatment may not be an option due to intolerance or refractoriness. Proliferation and survival of HCL cells is regulated by surrounding accessory cells and soluble signals present in the tumor microenvironment, which actively contributes to disease progression. In vitro studies show that different therapeutic approaches tested in HCL impact the tumor microenvironment, and that this milieu offers a protection affecting treatment efficacy. Herein we explore the effects of the tumor microenvironment to different approved and experimental therapeutic options for HCL. Dissecting the complex interactions between leukemia cells and their milieu will be essential to develop new targeted therapies for HCL patients.

Keywords: HCL; leukemia microenvironment; microenvironment targeting; novel therapies; treatment resistance.

Figure 1

The protective role of the tumor microenvironment against treatments in HCL. Approved and experimental therapeutic options for HCL are presented, and details of microenvironment-mediated protection are provided. (A) Cytokines. IFN-α treatment efficacy is reduced due to engagement of HC to FN or VN receptors, present in the extracellular matrix of the spleen and bone marrow, inhibiting the IFN-α-mediated downregulation of IAPs, ultimately leading to reduced cell death. (B) Purine analogs. Cladribine off-targets effects could reduce the immune response against HC, mediated by cytotoxic T- and NK cells, and increase the levels of IL-10, promoting an anti-inflammatory profile. Indirect expansion of monocytes and dendritic cells can further favor HC survival. (C) Anti-CD20 antibodies. Monoclonal antibody Rituximab efficacy could be highly reduced in HCL due to the secretion of leukemia- and normal B cell-derived CD20⁺ sEV, as well as the higher expression of CD20 on normal B cells. On the other hand, CD40-CD40L interaction leads to increased sensitivity towards Rituximab in CLL and this could also be the case in HCL. (D) BRAF and MECK inhibitors. The pro-apoptotic effect of vemurafenib and trametinib is reduced by the presence of stromal cells in the microenvironment, which impair the dephosphorylation changes induced by these drugs. (E) Recombinant immunotoxins. The effect of these molecules could be affected by microenvironment modulation of the surface targets, e.g. CD22 availability during CAT-8015 treatment; or increased, e.g. CD25 upregulation during LMB-2 treatment in presence of CpG-ODN. Apoptosis of off-target cells, as regulatory T cells in the case of LMB-2, could indirectly influence the efficacy of the treatment. (F) BTK inhibitors. Ibrutinib treatment is highly efficient in affecting HC, but reduces the secretion of CCL3 and CCL4, and impairs CXCR4 signaling. This could possibly lead to redistribution of HC and other supporting cells in the microenvironment, possibly influencing other treatment regiments. (G) CAR-T cells. Anti-CD22 CAR-T therapy can be impaired by TGF-β1, directly affecting engineered T cells, as well as inducing Treg expansion. High levels of IL-1 in HCL microenvironment enhance the risk of CRS. (H) BCL-2 inhibitors. Venetoclax treatment efficacy is strongly reduced against HC stimulated with TLR2 and TLR9 ligands, as well as by the presence of activated T and stromal cells. Created with BioRender.com.