Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape

Abstract

The quest for treatment-free remission (TFR) and deep molecular response (DMR) in chronic myeloid leukemia (CML) has been profoundly impacted by tyrosine kinase inhibitors (TKIs). Immunologic surveillance of residual leukemic cells is hypothesized to be one of the critical factors in successful TFR, with self-renewing leukemic stem cells implicated in relapse. Immunological characterization in CML may help to develop novel immunotherapies that specifically target residual leukemic cells upon TKI discontinuation to improve TFR rates. This review focuses on immune dysfunction in newly diagnosed CML patients, and the role that TKIs and other therapies have in restoring immune surveillance. Immune dysfunction and immunosurveillance in CML points towards several emerging areas in the key goals of DMR and TFR, including: (1) Aspects of innate immune system, in particular natural killer cells and the newly emerging target plasmacytoid dendritic cells. (2) The adaptive immune system, with promise shown in regard to leukemia-associated antigen vaccine-induced CD8 cytotoxic T-cells (CTL) responses, increased CTL expansion, and immune checkpoint inhibitors. (3) Immune suppressive myeloid-derived suppressor cells and T regulatory cells that are reduced in DMR and TFR. (4) Immunomodulator mesenchymal stromal cells that critically contribute to leukomogenesis through immunosuppressive properties and TKI- resistance. Therapeutic strategies that leverage existing immunological approaches include donor lymphocyte infusions, that continue to be used, often in combination with TKIs, in patients relapsing following allogeneic stem cell transplant. Furthermore, previous standards-of-care, including interferon-α, hold promise in attaining TFR in the post-TKI era. A deeper understanding of the immunological landscape in CML is therefore vital for both the development of novel and the repurposing of older therapies to improve TFR outcomes.

Fig. 1. Immunomodulatory effects of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients.

Upper diagram—CML effects on untreated immune cells. Lower diagram—effects on immune cells after TKI treatment, including cytotoxic T-cells (CTLs), natural killer (NK) cells, dendritic cells (DCs) and plasmacytoid DCs (pDCs), myeloid-derived suppressor cells (MDSCs), regulatory T-cells (Tregs), mesenchymal stromal cells (MSCs) and B-cells. LAAs leukemia-associated antigens, G-MDSCs granulocyte-like MDSCs, PD1 programmed death 1, TFR treatment-free remission, DMR deep molecular response (or MR⁴; BCR-ABL1 ≤ 0.01%), MR^4.5 molecular response^4.5 (BCR-ABL1 ≤ 0.0032%), CCR complete cytogenetic remission. Illustration was created with BioRender.com.

Fig. 2. The major natural killer (NK) cell receptors affected in chronic myeloid leukemia (CML).

Progression of NK cells from quiescence to activation is mediated by activating (in green) and inhibitory (in red) receptors. The balance between both receptor subtypes determines if NK cells are cytotoxic. The inhibitory killer cell immunoglobulin-like rectors (KIRs) and natural killer group 2A (NKG2A) receptor conduct inhibitory signals to restrain NK cell function to avoid killing normal cells under physiological conditions. In contrast, activating receptors such as natural cytotoxic receptors (NCRs)—NKp30, NKp46 and NKp80, and NKG2D trigger NK cell activation following binding to ligands upregulated on target cells undergoing stress and/or infection. PD1: programmed death 1. Illustration was created with BioRender.com.