Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Abstract

Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56^dim NK cells may be important in mediating TFR success. However, a major goal remains in CML to identify the most effective pathways to target to maximize an advantageous immune response and promote TFR success.

Keywords: chronic myeloid leukemia; deep molecular response; immune surveillance; immunology; treatment-free remission.

Figure 1

Immune effector recovery in CML patients achieving deep molecular response on TKI therapy. Diagnosis CP CML; suppression of the immune system in CP CML patients at diagnosis is mediated in part by hematopoietic stem cells, which acquire a proliferative/survival advantage and lose the ability to undergo apoptosis. Release of tumor-derived cytokines/chemokines drives the expansion of immune suppressor MDSC and Treg, facilitating downregulation of antitumor effector immunity. PD-L1 is upregulated on CML cells, where it interacts with the coinhibitory receptor PD-1, and contributes to protection of the malignant cells from immune destruction. MDSC originate from the malignant BCR-ABL1 clone and mediate their suppressive activity via a number of mechanisms, including increased production of reactive oxygen and nitrogen species (NO, ROS), arginase-1, and TGF-β1. MDSC can induce Treg expansion, and Treg also express PD-1 to promote enhanced suppressor function. Post-TKI treatment; TKI exert immunomodulatory effects, particularly against key suppressor MDSC and Treg populations, conferring immune system re-activation and restoring effector-mediated immune surveillance. More specifically, TKI treatment leads to restoration of NK cell receptor repertoire and enhanced NK cell function, restoration of LAA-CTL responses, including downregulation of PD-1 to normal levels, and increased DC number and antigen-presenting cell function. CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor; CP, chronic phase; MDSCs, myeloid-derived suppressor cells; Treg, regulatory T cells; PD-L1, programmed death ligand-1; PD-1, programmed death-1; NO, nitric oxide; ROS, reactive oxygen species; TGF-β1, transforming growth factor-β1; NK, natural killer; LAA, leukemia-associated antigen; CTL, cytotoxic T lymphocyte; DC, dendritic cell.