The Yin-Yang of myeloid cells in the leukemic microenvironment: Immunological role and clinical implications

Abstract

The leukemic microenvironment has a high diversity of immune cells that are phenotypically and functionally distinct. However, our understanding of the biology, immunology, and clinical implications underlying these cells remains poorly investigated. Among the resident immune cells that can infiltrate the leukemic microenvironment are myeloid cells, which correspond to a heterogeneous cell group of the innate immune system. They encompass populations of neutrophils, macrophages, and myeloid-derived suppressor cells (MDSCs). These cells can be abundant in different tissues and, in the leukemic microenvironment, are associated with the clinical outcome of the patient, acting dichotomously to contribute to leukemic progression or stimulate antitumor immune responses. In this review, we detail the current evidence and the many mechanisms that indicate that the activation of different myeloid cell populations may contribute to immunosuppression, survival, or metastatic dissemination, as well as in immunosurveillance and stimulation of specific cytotoxic responses. Furthermore, we broadly discuss the interactions of tumor-associated neutrophils and macrophages (TANs and TAMs, respectively) and MDSCs in the leukemic microenvironment. Finally, we provide new perspectives on the potential of myeloid cell subpopulations as predictive biomarkers of therapeutical response, as well as potential targets in the chemoimmunotherapy of leukemias due to their dual Yin-Yang roles in leukemia.

Keywords: immune response; immunotherapy; leukemia; macrophages; myeloid-derived suppressor cells; neutrophils; tumor microenvironment.

Figure 1

Regulation of TAN responses in the leukemic microenvironment. The figure shows the pro-tumor and antitumor activities of tumor-associated neutrophils (TANs), which provide critical signals for leukemic progression. This network of interactions between TANs, leukemic cells (LCs) and other immune cells [e.g., regulatory T cells (Treg)] results in four main events: [1] recruitment and/or mobilization of neutrophils via CXCL8/CXCR2 to the leukemic microenvironment, where LCs promote the survival of TANs through the release of G-CSF and GM-CSF; [2] reprogramming of TANs to become pro-tumor (N2) or antitumor (N1) cells through stimulation of the leukemic microenvironment through the cytokines IL-10 and TGF-β; [3] immunosuppression promoted by N2 TANs that can preferentially recruit Treg cells and can suppress T cell effector responses, apparently via a PD1-PDL1-mediated pathway; [4] LC proliferation and survival in the leukemic microenvironment regulated by a range of surface molecules (e.g., BAFF and APRIL) expressed by N2 TANs, which also release NETs, which, in turn, delay LC apoptosis; [5] In another scenario, the oxidative burst triggered by N1 TANs can promote the release of reactive oxygen species (ROS) that control proliferation or mediate the killing of LCs. APRIL, A proliferation-inducing ligand; BAFF, B-cell activating factor; G-CSF, granulocyte colony-stimulating-factor; GM-CSF, Human granulocyte-macrophage colony-stimulating factor; NETs, ​​Neutrophil extracellular traps; PD1, Programmed cell death protein 1; PDL1, Programmed cell death-ligand 1; TGF-β, Transforming growth factor-β.

Figure 2

Regulation of TAM responses in the leukemic microenvironment. The figure shows the pro-tumor and antitumor activities of tumor-associated macrophages (TAMs), which are critical signs for leukemic progression. This network of interactions between TAMs, LCs and other immune cells [e.g., NK cells and Treg cells] results in five main events: [1] recruitment and/or mobilization of monocytes via CXCL8/CXCR2 and CCL2/CCR2 to the leukemic microenvironment, which differentiate into TAMs; [2] reprogramming TAMs to become pro-tumor (M2) or antitumor (M1) cells through many stimuli from the leukemic microenvironment, such as cytokines and cell-cell crosstalk (i.e., context dependent); [3] immune interactions with LCs within the leukemic microenvironment through a wide range of surface molecules that send many signals to stimulate the proliferation, survival and chemoresistance in LCs (e.g., BAFF, APRIL, CD31, Plexin-B1 and CD2); [4] establishment of a strongly tolerogenic environment, such as M2 TAMs, which produce many suppressive cytokines (e.g., IL-10 and TGF-β) and express immune checkpoints (PDL1 and/or PDL2), and which regulate the responses of T NK cells, and stimulate Treg cell activities; [5] establishment of an inflammatory environment, such as M1 TAMs, thus stimulating the cytotoxic activity of T and NK cells by the production of inflammatory cytokines (e.g., TNF and IL-12) and the expression of co-stimulatory molecules (e.g., CD80, CD86 and HLA-DR), which can promote antitumor responses and the death of the tumor. APRIL, A proliferation-inducing ligand; BAFF, B-cell activating factor; BAFF-R, BAFF receptor; BCMA, B-cell maturation antigen; CCR2, C-C motif chemokine receptor 2; CXCR4, C-X-C chemokine receptor 4; HLA-DR, Human leukocyte antigen DR; LFA-3, Lymphocyte function-associated antigen 3; NK, Natural killer; PD1, Programmed cell death protein 1.

Figure 3

Regulation of MDSC responses in the leukemic microenvironment. The figure shows the origin and pro-tumor activities of myeloid-derived suppressor cells (MDSCs), which provide critical signals for leukemic progression. This network of interactions between MDSCs, LCs, and other immune cells [e.g., T cells, NK cells, and Treg cells] results in four main events: [1] emergence of MDSCs in bone marrow from common myeloid progenitor cells that differentiate into PMN-MDSC and M-MDSC after persistent inflammatory signals, thus characterizing a process known as “emergency myelopoiesis”; [2] activation and recruitment of Treg cells through the release of regulatory cytokines (e.g., IL-10, TGF-β), which contribute to immunosuppression of the leukemic microenvironment;[3] exhaustion of T and NK cells from different inflammatory (e.g., IL-6, TNF and IL-1β) and/or anti-inflammatory (e.g., IL-10, TGF-β, Arg1, IDO and iNOS) mediators and surface molecules (PDL1 or VISTA) expressed by MDSCs, which regulate antitumor responses;[4] LC proliferation and survival, which are a consequence of suppression of T cell and NK cell effector responses and activation of Treg cells in the leukemic microenvironment. Arg1, Arginase 1; IDO, Indoleamine; iNOS, nitric oxide synthase; M-MDSC, monocytic-MDSC; NK, Natural killer; PDL1, Programmed death-ligand 1; PMN-MDSC, polymorphic mononuclear-MDSC; TGF-β, Transforming growth factor beta; TNF, Necrosis factor tumoral; Treg, Regulatory T cells; VISTA, V-domain Ig suppressor of T cell activation.

Figure 4

Yin-Yang with the dual role (pro and antitumor) of myeloid cells in the leukemic microenvironment. In leukemia, the different subsets of myeloid cells (TANs, TAMs and MDSCs) can exert dichotomous functions dictated by the polarization status of each cell. The pro-tumor phenotype is highlighted by the presence of N2 TANs, M2 TAMs and MDSCs, which show strong immunosuppressive activity through the production of anti-inflammatory mediators and formation of leukemic niches that contribute to the increase in tumor burden. In contrast, the antitumor phenotype involves the presence of N1 TANs and M1 TAMs that can exert protective functions through the release of cytotoxic mediators, tumor antigen presentation, death or phagocytosis of leukemic cells.