Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis.
ABSTRACT: Immunotherapy aiming to rescue or boost antitumor immunity is an emerging strategy for treatment of cancers. The efficacy of immunotherapy is strongly controlled by the immunological milieu of cancer patients. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cell populations with immunosuppressive functions accumulating in individuals during tumor progression. The signaling mechanisms of MDSC activation have been well studied. However, there is little known about the metabolic status of MDSCs and the physiological role of their metabolic reprogramming. In this study, we discovered that myeloid cells upregulated their glycolytic genes when encountered with tumor-derived factors. MDSCs exhibited higher glycolytic rate than their normal cell compartment did, which contributed to the accumulation of the MDSCs in tumor-bearing hosts. Upregulation of glycolysis prevented excess reactive oxygen species (ROS) production by MDSCs, which protected MDSCs from apoptosis. Most importantly, we identified the glycolytic metabolite, phosphoenolpyruvate (PEP), as a vital antioxidant agent able to prevent excess ROS production and therefore contributed to the survival of MDSCs. These findings suggest that glycolytic metabolites have important roles in the modulation of fitness of MDSCs and could be potential targets for anti-MDSC strategy. Targeting MDSCs with analogs of specific glycolytic metabolites, for example, 2-phosphoglycerate or PEP may diminish the accumulation of MDSCs and reverse the immunosuppressive milieu in tumor-bearing individuals.
Project description:Among the various immunological and non-immunological tumor-promoting activities of myeloid-derived suppressor cells (MDSCs), their immunosuppressive capacity remains a key hallmark. Effort in the past decade has provided us with a clearer view of the suppressive nature of MDSCs. More suppressive pathways have been identified, and their recognized targets have been expanded from T cells and natural killer (NK) cells to other immune cells. These novel mechanisms and targets afford MDSCs versatility in suppressing both innate and adaptive immunity. On the other hand, a better understanding of the regulation of their development and function has been unveiled. This intricate regulatory network, consisting of tumor cells, stromal cells, soluble mediators, and hostile physical conditions, reveals bi-directional crosstalk between MDSCs and the tumor microenvironment. In this article, we will review available information on how MDSCs exert their immunosuppressive function and how they are regulated in the tumor milieu. As MDSCs are a well-established obstacle to anti-tumor immunity, new insights in the potential synergistic combination of MDSC-targeted therapy and immunotherapy will be discussed.
Project description:Pancreatic cancer is characterized by an immunosuppressive tumor microenvironment (TME) with a profound immune infiltrate populated by a significant number of myeloid-derived suppressor cells (MDSCs). MDSCs have been increasingly recognized for their role in immune evasion and cancer progression as well as their potential as a target for immunotherapy. However, not much is known about the mechanisms regulating their behavior and function in the pancreatic TME. Here we report that pancreatic adenocarcinoma up-regulated factor (PAUF), a soluble protein involved in pancreatic tumorigenesis and metastasis, plays a role as an enhancer of tumor-infiltrating MDSC and its functional activity. We show that PAUF enhanced the accumulation of MDSCs in the spleen and tumor tissues of PAUF-overexpressing tumor cell-injected mice. In addition, PAUF was found to enhance the immunosuppressive function of MDSCs via the TLR4-mediated signaling pathway, which was demonstrated by PAUF-induced increased levels of arginase, nitric oxide (NO), and reactive oxygen species (ROS). The role of PAUF in modulating the functional properties of MDSCs was further demonstrated by the use of a PAUF-neutralizing antibody that caused a decreased number of tumor-infiltrating MDSCs and reduced MDSC immunosuppressive activity. The observations made in mice were confirmed in human pancreatic cancer patient-derived MDSCs, supporting the clinical relevance of our findings. Collectively, we conclude that the PAUF is a powerful and multifunctional promoter of tumor growth through increase and functional activation of MDSCs, suggesting therapeutic potential for targeting PAUF in pancreatic cancers.
Project description:Fas ligand expression in certain tumors has been proposed to contribute to immunosuppression and poor prognosis. However, immunotherapeutic approaches may elicit the Fas-mediated elimination of immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within tumors that represent major obstacles for cancer immunotherapy. Previously, we showed that IL-2 and agonistic CD40 Ab (?CD40) elicited synergistic antitumor responses coincident with the efficient removal of Tregs and MDSCs. We demonstrate in this study in two murine tumor models that Treg and MDSC loss within the tumor microenvironment after IL-2/?CD40 occurs through a Fas-dependent cell death pathway. Among tumor-infiltrating leukocytes, CD8(+) T cells, neutrophils, and immature myeloid cells expressed Fas ligand after treatment. Fas was expressed by tumor-associated Tregs and immature myeloid cells, including MDSCs. Tregs and MDSCs in the tumor microenvironment expressed active caspases after IL-2/?CD40 therapy and, in contrast with effector T cells, Tregs significantly downregulated Bcl-2 expression. In contrast, Tregs and MDSCs proliferated and expanded in the spleen after treatment. Adoptive transfer of Fas-deficient Tregs or MDSCs into wild-type, Treg-, or MDSC-depleted hosts resulted in the persistence of Tregs or MDSCs and the loss of antitumor efficacy in response to IL-2/?CD40. These results demonstrate the importance of Fas-mediated Treg/MDSC removal for successful antitumor immunotherapy. Our results suggest that immunotherapeutic strategies that include exploiting Treg and MDSC susceptibility to Fas-mediated apoptosis hold promise for treatment of cancer.
Project description:Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate during tumor formation, facilitate immune escape, and enable tumor progression. MDSCs are important contributors to the development of an immunosuppressive tumor microenvironment that blocks the action of cytotoxic antitumor T effector cells. Heterogeneity in these cells poses a significant barrier to studying the in vivo contributions of individual MDSC subtypes. Herein, we show that granulocyte-macrophage colony stimulating factor, a cytokine critical for the numeric and functional development of MDSC populations, promotes expansion of a monocyte-derived MDSC population characterized by expression of CD11b and the chemokine receptor CCR2. Using a toxin-mediated ablation strategy to target CCR2-expressing cells, we show that these monocytic MDSCs regulate entry of activated CD8 T cells into the tumor site, thereby limiting the efficacy of immunotherapy. Our results argue that therapeutic targeting of monocytic MDSCs would enhance outcomes in immunotherapy.
Project description:Abstract Lack of tumor?infiltration lymphocytes (TILs) and resistances by overexpressed immunosuppressive cells (principally, myeloid?derived suppressor cells (MDSCs)) in tumor milieu are two major challenges hindering the effectiveness of immunotherapy for “immune?cold” tumors. In addition, the natural physical barrier existing in solid cancer also limits deeper delivery of drugs. Here, a tumor?targeting and light?responsive?penetrable nanoplatform (Apt/PDGs^s@pMOF) is developed to elicit intratumoral infiltration of cytotoxic T cells (CTLs) and reeducate immunosuppressive microenvironment simultaneously. In particular, porphyrinic metal–organic framework (pMOF)–based photodynamic therapy (PDT) induces tumor immunogenic cell death (ICD) to promote CTLs intratumoral infiltration and hot “immune?cold” tumor. Upon being triggered by PDT, the nearly 10 nm adsorbed drug?loaded dendrimer de?shields from the nanoplatform and spreads into the deeper tumor, eliminating MDSCs and reversing immunosuppression, eventually reinforcing immune response. Meanwhile, the designed nanoplatform also has a systemic MDSC inhibition effect and moderate improvement of overall antitumor immune responses, resulting in effective suppression of distal tumors within less significant immune?related adverse effects (irAEs) induced. A penetrable nanoplatform is developed to elicit intratumoral infiltration of cytotoxic T cells (CTLs) and reeducate immunosuppressive microenvironment simultaneously. In particular, immunogenic cell death induced by photodynamic therapy (PDT) promotes CTLs infiltration, upon being triggered by PDT, drug?loaded dendrimer spreads into deeper tumor, eliminating myeloid?derived suppressor cells and reversing immunosuppression, eventually reinforcing immune responses.
Project description:The goal of achieving measurable response with cancer immunotherapy requires counteracting the immunosuppressive characteristics of tumors. One of the mechanisms that tumors utilize to escape immunosurveillance is the activation of myeloid derived suppressor cells (MDSCs). Upon activation by tumor-derived signals, MDSCs inhibit the ability of the host to mount an anti-tumor immune response via their capacity to suppress both the innate and adaptive immune systems. Despite their relatively recent discovery and characterization, anti-MDSC agents have been identified, which may improve immunotherapy efficacy.
Project description:Radiotherapy (RT) has been used for decades as one of the main treatment modalities for cancer patients. The therapeutic effect of RT has been primarily ascribed to DNA damage leading to tumor cell death. Besides direct tumoricidal effect, RT affects antitumor responses through immune-mediated mechanism, which provides a rationale for combining RT and immunotherapy for cancer treatment. Thus far, for the combined treatment with RT, numerous studies have focused on the immune checkpoint inhibitors and have shown promising results. However, treatment resistance is still common, and one of the main resistance mechanisms is thought to be due to the immunosuppressive tumor microenvironment where myeloid-derived suppressor cells (MDSCs) play a crucial role. MDSCs are immature myeloid cells with a strong immunosuppressive activity. MDSC frequency is correlated with tumor progression, recurrence, negative clinical outcome, and reduced efficacy of immunotherapy. Therefore, increasing efforts to target MDSCs have been made to overcome the resistance in cancer treatments. In this review, we focus on the role of MDSCs in RT and highlight growing evidence for targeting MDSCs in combination with RT to improve cancer treatment.
Project description:Tumor-induced, myeloid-derived suppressor cells (MDSCs)-mediated immune dysfunction is an important mechanism that leads to tumor immune escape and the inefficacy of cancer immunotherapy. Importantly, tumor-infiltrating MDSCs have much stronger ability compared to MDSCs in the periphery. However, the mechanisms that tumor microenvironment induces the accumulation and function of MDSCs are poorly understood. Here, we report that Interleukin-33 (IL-33) - a cytokine which can be abundantly released in tumor tissues both in 4T1-bearing mice and breast cancer patients, is crucial for facilitating the expansion of MDSCs. IL-33 in tumor microenvironment reduces the apoptosis and sustains the survival of MDSCs through induction of autocrine secretion of GM-CSF, which forms a positive amplifying loop for MDSC accumulation. This is in conjunction with IL-33-driven induction of arginase-1 expression and activation of NF-?B and MAPK signaling in MDSCs which augments their immunosuppressive ability, and histone modifications were involved in IL-33 signaling in MDSCs. In ST2-/- mice, the defect of IL-33 signaling in MDSCs attenuates the immunosuppressive and pro-tumoral capacity of MDSCs. Our results identify IL-33 as a critical mediator that contributes to the abnormal expansion and enhanced immunosuppressive function of MDSCs within tumor microenvironment, which can be potentially targeted to reverse MDSC-mediated tumor immune evasion.
Project description:CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs) play critical roles in controlling the processes of tumors, infections, autoimmunity and graft rejection. Immunosuppressive drug rapamycin (RPM), targeting on the key cellular metabolism molecule mTOR, is currently used in clinics to treat patients with allo-grafts, autoimmune diseases and tumors. However, the effect of RPM on MDSCs has not been studied. RPM significantly decreases the cell number and the immunosuppressive ability on T cells of CD11b(+) Ly6C(high) monocytic MDSCs (M-MDSCs) in both allo-grafts-transplanted and tumor-bearing mice respectively. Mice with a myeloid-specific deletion of mTOR have poor M-MDSCs after grafting with allo-skin tissue or a tumor. Grafting of allo-skin or tumors significantly activates glycolysis pathways in myeloid precursor cells in bone marrow, which is inhibited by RPM or mTOR deletion. 2-deoxyglucose (2-DG), an inhibitor of the glycolytic pathway, inhibits M-MDSC differentiation from precursors, while enhancing glycolysis by metformin significantly rescues the RPM-caused deficiency of M-MDSCs. Therefore, we offer evidence supporting that mTOR is an intrinsic factor essential for the differentiation and immunosuppressive function of M-MDSCs and that these metabolism-relevant medicines may impact MDSCs-mediated immunosuppression or immune tolerance induction, which is of considerable clinical importance in treating graft rejection, autoimmune diseases and cancers.
Project description:Myeloid-derived suppressor cells (MDSCs) are immature monocytes and granulocytes that impede immune-mediated clearance of malignant cells by multiple mechanisms, including the formation of immunosuppressive reactive oxygen species (ROS) via the myeloid cell NADPH oxidase (NOX2). Histamine dihydrochloride (HDC), a NOX2 inhibitor, exerts anti-cancer efficacy in experimental tumor models but the detailed mechanisms are insufficiently understood. To determine effects of HDC on the MDSC compartment we utilized three murine cancer models known to entail accumulation of MDSC, i.e. EL-4 lymphoma, MC-38 colorectal carcinoma, and 4T1 mammary carcinoma. In vivo treatment with HDC delayed EL-4 and 4T1 tumor growth and reduced the ROS formation by intratumoral MDSCs. HDC treatment of EL-4 bearing mice also reduced the accumulation of intratumoral MDSCs and reduced MDSC-induced suppression of T cells ex vivo. Experiments using GR1-depleted and Nox2 knock out mice supported that the anti-tumor efficacy of HDC required presence of NOX2+ GR1+ cells in vivo. In addition, treatment with HDC enhanced the anti-tumor efficacy of programmed cell death receptor 1 (PD-1) and PD-1 ligand checkpoint blockade in EL-4- and MC-38-bearing mice. Immunomodulatory effects of a HDC-containing regimen on MDSCs were further analyzed in a phase IV trial (Re:Mission Trial, ClinicalTrials.gov; NCT01347996) where patients with acute myeloid leukemia received HDC in conjunction with low-dose IL-2 (HDC/IL-2) for relapse prevention. Peripheral CD14+HLA-DR-/low MDSCs (M-MDSCs) were reduced during cycles of HDC/IL-2 therapy and a pronounced reduction of M-MDSCs during HDC/IL-2 treatment heralded favorable clinical outcome. We propose that anti-tumor properties of HDC may comprise the targeting of MDSCs.