cancers Review Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development Tomasz M. Grzywa 1,2,3 , Magdalena Justyniarska 1, Dominika Nowis 3,* and Jakub Golab 1,* 1 Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; [email protected] (T.M.G.); [email protected] (M.J.) 2 Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland 3 Laboratory of Experimental Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland * Correspondence: [email protected] (D.N.); [email protected] (J.G.) Simple Summary: Tumor immune evasion is one of the hallmarks of tumor progression that enables tumor growth despite the activity of the host immune system. It is mediated by various types of cells. Recently, immature red blood cells called erythroid progenitor cells (EPCs) were identified as regulators of the immune response in cancer. EPCs expand in cancer as a result of dysregulated erythropoiesis and potently suppress the immune response. Thus, targeting dysregulated EPC differentiation appears to be a promising therapeutic strategy. Abstract: Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), Citation: Grzywa, T.M.; Justyniarska, erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and M.; Nowis, D.; Golab, J. Tumor tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red Immune Evasion Induced by blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. Dysregulation of Erythroid EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), Progenitor Cells Development. interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress Cancers 2021, 13, 870. https:// T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune doi.org/10.3390/cancers13040870 suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to Academic Editor: Alberto Anel the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting Received: 20 January 2021 ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce Accepted: 15 February 2021 cancer-induced immunosuppression and the tumor-promoting effects of EPCs. Published: 19 February 2021 Keywords: immune evasion; erythroid progenitor cells; CD71+ erythroid cells; erythropoiesis; Publisher’s Note: MDPI stays neutral anemia; Ter-cells; ineffective erythropoiesis with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Cancer immunotherapy has strongly changed the therapeutic landscape in clinical oncology, leading to significant improvements in cancer patients survival [1]. However, de- Copyright: © 2021 by the authors. spite the induction of durable responses in an unprecedented percentage of cancer patients, Licensee MDPI, Basel, Switzerland. the majority still do not respond to the treatment and eventually progress to refractory This article is an open access article disease. There are several defined causes of immunotherapy resistance, including low distributed under the terms and tumor mutational burden [2], impaired antigen presentation by the major histocompatibil- conditions of the Creative Commons ity complex (MHC) proteins [3], loss of interferon-γ (IFN-γ) and tumor necrosis factor-α Attribution (CC BY) license (https:// (TNF-α) pathway genes [4,5], as well as the development of immunosuppressive tumor creativecommons.org/licenses/by/ microenvironment (TME) [6,7]. 4.0/). Cancers 2021, 13, 870. https://doi.org/10.3390/cancers13040870 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 870 2 of 33 TME is composed of many types of cells that regulate tumor growth and progression [8]. The role of regulatory T-cells (Tregs) [9], myeloid-derived suppressor cells (MDSCs) [10], tumor-associated macrophages (TAMs) [11], tumor-associated neutrophils (TANs) [12], and cancer-associated fibroblasts (CAFs) [13] in the regulation of anti-tumor immune response has been established by many years of research (Table1). Recent reports point to another population of cells, i.e., erythroid progenitor cells (EPCs), that regulate local and systemic immunity in cancer. These cells use similar mechanisms to immune cells and are crucial in the regulation of immune response and cancer progression. Table 1. Immunomodulatory cells in cancer and their mechanisms of immune regulation. Cells Mechanisms Effects Ref IL-10 T-cell suppression [14] Regulatory T-cells IL-2 consumption T-cell suppression [15] (Tregs) COX-2 and PGE2 T-cell suppression [16] Adenosine T-cell suppression [17] ARG1 T-cell suppression [18] T-cell suppression IDO Tregs induction [19,20] NK cell suppression PD-L1/PD-1 T-cell suppression [21] Myeloid-derived IL-10 Tregs induction [22] suppressor cells TGF-β Tregs induction [22] (MDSCs) CD40/CD40L Tregs activation [23] Depletion of cystine and cysteine T-cell suppression [24] ROS T-cell suppression [25] Resistance to Free radical peroxynitrite [26] cytotoxic T-cells Decreased PD-L1/PD-1 [27] phagocytosis ARG1 T-cell suppression [28] IL-10 T-cell suppression [29] Tumor associated MDSC infiltration macrophages (TAMs) IL-1β Induction of the [30,31] protumor phenotype Induction of T-cell IL-12 [32] response Induction of TNF-α [33] anti-tumor response ARG1 T-cell suppression [18,28] Tumor associated T-cell suppression NOS [34,35] neutrophils (TANs) T-cell apoptosis PD-L1/PD-1 T-cell suppression [36] PD-L1/PD-1 T-cell suppression [37] FasL, PD-L2 T-cell suppression [38] Cancer associated Induction of PD-L1+ fibroblasts (CAFs) IL-6 [39] TANs Chemokines MDSC infiltration [40] ROS T-cell suppression [41,42] Erythroid progenitor IL-10 T-cell suppression [42] cells (EPCs) PD-L1/PD-1 T-cell suppression [43] TGF-β T-cell suppression [42] ARG1—arginase 1, COX-2—cyclooxygenase-2, FasL—Fas ligand (CD95L, CD178), IDO—Indoleamine-pyrrole 2,3-dioxygenase, IL—interleukin, NK—natural killer, NOS—nitric oxide synthase, PD-1—programmed cell death 1, PD-L1—programmed death-ligand 1, PGE2—Prostaglandin E2, ROS—reactive oxygen species, TGF-β—transforming growth factor β, TNF-α—tumor necrosis factor α. Cancers 2021, 13, 870 3 of 33 In this review, we discuss the role of the dysregulation of erythropoiesis by cancer cells to induce immune evasion and promote cancer progression. 2. Regulation of Erythropoiesis The differentiation of hematopoietic stem cells (HSCs) to erythroid cells is a stepwise process strictly regulated by multiple intrinsic and extrinsic factors (Table2), which results in the production of over 2 × 1011 red blood cells (RBCs) per day and allows for the maintenance of erythroid homeostasis [44–48]. This complex net of interactions provides adequate production of RBCs depending on the body’s needs. Insufficient oxygen supply to the peripheral tissues resulting in hypoxia is a key trigger of increased erythropoiesis, which is regulated by the increased production of erythropoietin (EPO) in the kidney peritubular fibroblasts and liver interstitial cells and hepatocytes [49]. Table 2. Regulation of erythropoiesis. Factor Role in Erythropoiesis Dysregulation in Cancer References SCF Growth factors regulating Production in TME [50,51] G-CSF early stages of Increased serum [52] IL-3 erythropoiesis concentration [53] Increased serum EPO [54] Growth factors regulating concentration GDF11late stages of erythropoiesis Production in TME [55] Activin A Production in TME [56] Decreased expression in GATA1 Crucial TFs regulating [57–59] EPCs in cancer erythropoiesis Increased in EPCs in MPNs STAT5 Decreased in EPCs in [60,61] iron deficiency MCL-1 Survival factors for BCL-xL erythroid cells HSP70 Production in TME TGF-β [62] Increased concentration Increased level in EPCs SMAD signaling Negative regulators [62] in cancer of erythropoiesis High expression on FasL [59,63] cancer cells Increased level in EPCs Fas [59,63] in cancer Decreased in a subset Vitamin B12 [64] of patients Decreased in a subset Folic Acid [64] of patients CopperEssential vitamins, trace Increased concentration [65] elements, and Decreased in a subset Iron [66] iron-metabolism proteins of patients Ferritin Decreased or increased [66] Decreased in a subset Transferrin [66] of patients Ferroportin Decreased expression [67] Hepcidin Increased concentration [68] MPN—myeloproliferative neoplasm, TF—transcription factor, TME—tumor microenvironment. HSCs reside in a unique niche that is created and regulated by various cell types, growth factors, and chemokines [69]. The commitment of HSCs to erythroid lineage begins with the differentiation to a multipotent megakaryocyte–erythroid progenitor cell (MEP), followed by a bust-forming unit-erythroid (BFU-E) and colony-forming unit-erythroid Cancers 2021, 13, 870 4 of 33 (CFU-E). During terminal erythropoiesis, CFU-E differentiates into proerythroblasts,