Targeting Myeloid-derived Suppressor Cells Research Articles

Targeting myeloid-derived suppressor cells promotes antiparasitic T-cell immunity and enhances the efficacy of PD-1 blockade (15 words)

Immune exhaustion corresponds to a loss of effector function of T cells that associates with cancer or chronic infection. Here, our objective was to decipher the mechanisms involved in the immune suppression of myeloid-derived suppressor cells (MDSCs) and to explore the potential to target these cells for immunotherapy to enhance checkpoint blockade efficacy in a chronic parasite infection. We demonstrated that programmed cell-death-1 (PD-1) expression was significantly upregulated and associated with T-cell dysfunction in advanced alveolar echinococcosis (AE) patients and in Echinococcus multilocularis-infected mice. PD-1 blockade ex vivo failed to reverse AE patients’ peripheral blood T-cell dysfunction. PD-1/PD-L1 blockade or PD-1 deficiency had no significant effects on metacestode in mouse model. This was due to the inhibitory capacities of immunosuppressive granulocytic MDSCs (G-MDSCs), especially in the liver surrounding the parasite pseudotumor. MDSCs suppressed T-cell function in vitro in an indoleamine 2, 3 dioxygenase 1 (IDO1)-dependent manner. Although depleting MDSCs alone restored T-cell effector functions and led to some limitation of disease progression in E. multilocularis-infected mice, combination with PD-1 blockade was better to induce antiparasitic efficacy. Our findings provide preclinical evidence in support of targeting MDSC or combining such an approach with checkpoint blockade in patients with advanced AE. (200 words)

Sequence of androgen receptor-targeted vaccination with androgen deprivation therapy affects anti-prostate tumor efficacy

RationaleAndrogen deprivation therapy (ADT) is the primary treatment for recurrent and metastatic prostate cancer. In addition to direct antitumor effects, ADT has immunomodulatory effects such as promoting T-cell infiltration and...

Abstract 6345: In vitro characterization of a dual antagonistic anti-LILRB2/LILRB4 monoclonal antibody

Abstract Introduction: Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are a potential therapeutic target in immune checkpoint cancer therapy, but MDSC-targeted therapies have yet been shown to improve survival. The leukocyte immunoglobulin (Ig)-like receptor B2 is a member of the leukocyte Ig-like receptor (LILR) family and is predominantly expressed on the surface of cells of the myelomonocytic lineage (monocytes, macrophages and dendritic cells). LILRB2 is a negative regulator of myeloid cells and is an immune checkpoint receptor. We chose to generate mAbs against LILRB2 as a potential immunotherapeutic for cancer. Methods: PentaMice® strains (5 WT mouse strains comprising 9 MHC class II haplotypes to maximize Ab diversity) were immunized with human LILRB2. Lymphocytes were fused with a myeloma partner to generate lead monoclonal hybridomas. 24 purified anti-LILRB2 mAbs were generated and evaluated by arrayed surface plasma resonance (SPR, Carterra® LSA® instrument) to assign epitope bins. mAb humanization was performed in silico to maximize T20 “humanness” scores (algorithm developed by Curia). Humanized mAbs were transiently expressed using Curia’s TunaCHO™ platform and tested in in vitro MDSC assays. Autologous co-cultures of magnetic bead enriched-human blood-derived MDSC (HLA-DR-CD14+) model cells and T cells (CD3+) were stimulated with plate-bound anti-CD3/CD28 to induce T cell activation. Cytokine secretion was assessed 4 days later. Results: A total of 384 hybridoma supernatants were selected from the primary screen. 245 were confirmed by ELISA and 178 stained HEK293 cells expressing LILRB2 cells by flow cytometry (FACS). 24 hybridomas were further selected, cloned and sequenced. Five epitope bins were identified via Carterra® LSA® instrument. Two clones were chosen for humanization, designated 6-I11A and 4-O19A and were recombinantly expressed with the human IgG4 isotype. FACS analysis on HEK293 cells expressing either huLILRB2 or huLILRB4 revealed that clone hu4-O19A-IgG4 was specific for huLILRB2. Surprisingly, clone hu6-I11A-IgG4 stained both huLILRB2 and huLILRB4. FACS analysis with hu4-O19A-IgG4 on human MDSCs exhibited an EC50 of 11.9 nM and a KD of 1.5 nM in binding to recombinant huLILRB2 antigen, while hu6-I11A-IgG4 had an EC50 of 3.2 nM and a KD of 0.6 nM. In co-cultures with human MDSCs and T cells, both hu6-I11A-IgG4 and hu4-O19A-IgG4 reversed cytokine suppression by the MDSCs by increasing GM-CSF, IL-10, TNFα, and IL-6, while suppressing IL-13, and had little effect on IL-17A, MIP-3α, IL-4, IL-2 and IFNγ compared to treatment with the isotype control, with hu6-I11A-IgG4 having a greater effect as an antagonist than hu4-O19A-IgG4. Conclusions: We have identified a dual anti-LILRB2/LILRB4 antagonist. Targeting MDSCs with this antibody offers great promise for immunotherapy for cancer as well as its immense potential for synergy with PD-1 blockade. Citation Format: Bruce L. Daugherty, Xiaomei Ge, Christine L. Hsieh, Brian A. Zabel, Seth Lederman. In vitro characterization of a dual antagonistic anti-LILRB2/LILRB4 monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6345.

MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade

Immune checkpoint inhibitors (ICIs) are now the first-line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies. However, there are limited studies on the immunomodulatory role of the BH3 mimetics. Several factors contribute to ICI resistance including myeloid-derived suppressor cells (MDSCs) that exert immunosuppressive effects through direct and indirect inhibition of antitumor immunity. Thus, targeting MDSCs to enhance antitumor immunity has the potential to enhance the efficacy of ICIs. In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell-dependent manner in mice. Specifically, S64315 enhances antitumor immunity by reducing MDSC frequency and by promoting the activity of CD8+T cells. Additionally, human MDSCs are 10 times more sensitive to S64315 than cutaneous melanoma lines. Further, we found that a higher expression of MCL1 is associated with poor survival for patients treated with anti-PD-1. Finally, combining S64315 and anti-PD-1 significantly slowed tumor growth compared to either agent alone. Together, this proof-of-concept study demonstrates the potential of combining an MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.

MDSC-targeted liposomal all-trans retinoic acid suppresses mMdscs and improves immunotherapy in HBV infection

ABSTRACT Background Myeloid-derived suppressor cells (MDSCs) are evolving as a prominent determinant in cancer occurrence and development and are functionally found to suppress T cells in cancer. Not much research is done regarding its involvement in viral infections. This research was designed to investigate the role of MDSCs in hepatitis B virus (HBV) infection and how targeting these cells with our novel all-trans retinoic acid encapsulated liposomal formulation could improve immunotherapy in C57BL/6 mice. Methods Ten micrograms (10 μg) of plasmid adeno-associated virus (pAAV/HBV 1.2, genotype A) was injected hydrodynamically via the tail vein of C57BL/6 mice. An all-trans retinoic acid encapsulated liposomal formulation (L-ATRA) with sustained release properties was used in combination with tenofovir disoproxil fumarate (TDF), a nucleotide analog reverse transcriptase inhibitor (nRTI) to treat the HBV infection. The L-ATRA formulation was given at a dose of 5 mg/kg intravenously (IV) twice a week. The TDF was given orally at 30 mg/kg daily. Results Our results revealed that L-ATRA suppresses MDSCs in HBV infected mice and enhanced T-cell proliferation in vitro. In vivo studies showed higher and improved immunotherapeutic effect in mice that received L-ATRA and TDF concurrently in comparison with the groups that received monotherapy. Lower HBV DNA copies, lower concentrations of HBsAg and HBeAg, lower levels of ALT and AST and less liver damage were seen in the mice that received the combination therapy of L-ATRA + TDF. Conclusions In effect, targeting MDSCs with the combination of L-ATRA and TDF effectively reduced mMDSC and improved immunotherapy in the HBV infected mice. Targeting MDSCs could provide a breakthrough in the fight against hepatitis B virus infection.

Nanomedicine Targeting Myeloid-Derived Suppressor Cells Enhances Anti-Tumor Immunity.

Cancer immunotherapy, a field within immunology that aims to enhance the host's anti-cancer immune response, frequently encounters challenges associated with suboptimal response rates. The presence of myeloid-derived suppressor cells (MDSCs), crucial constituents of the tumor microenvironment (TME), exacerbates this issue by fostering immunosuppression and impeding T cell differentiation and maturation. Consequently, targeting MDSCs has emerged as crucial for immunotherapy aimed at enhancing anti-tumor responses. The development of nanomedicines specifically designed to target MDSCs aims to improve the effectiveness of immunotherapy by transforming immunosuppressive tumors into ones more responsive to immune intervention. This review provides a detailed overview of MDSCs in the TME and current strategies targeting these cells. Also the benefits of nanoparticle-assisted drug delivery systems, including design flexibility, efficient drug loading, and protection against enzymatic degradation, are highlighted. It summarizes advances in nanomedicine targeting MDSCs, covering enhanced treatment efficacy, safety, and modulation of the TME, laying the groundwork for more potent cancer immunotherapy.

Abstract A031: Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) has a 5-year survival rate of only 10%, and limited treatment options exist. Immune checkpoint inhibitors are effective in a variety of cancer types; however, the complex immunosuppressive tumor microenvironment (TME) of PDAC is a significant barrier to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are abundant in PDAC tumors from humans and mouse models. MDSCs suppress effector T cell function and promote the expansion of other immunosuppressive cell types. This led us to hypothesize that targeting tumor MDSCs would be an effective therapeutic strategy for PDAC and enhance the efficacy of T cell based immunotherapy. Our preliminary data and the work from others shows that CXCR2 ligands such as CXCL8/IL-8, CXCL5/ENA78, and CXCL1/GROα are the most abundant soluble factors secreted by PDAC cells. CXCR2 ligands are critical for the homing of myeloid cells to sites of injury in cutaneous wound healing, suggesting that dysregulated secretion of CXCR2 chemokines in PDAC may mimic a wound healing response that attracts myeloid cells and promotes the expansion of MDSCs and an immunosuppressive TME. To test this hypothesis, we have designed and produced multiple drug-conjugated CXCR2 ligand-based engineered proteins to target and eliminate MDSCs from PDAC tumors. We are referring to these novel biotherapeutic molecules as Ligand Drug Conjugates (LDCs). We have demonstrated binding, internalization, induction of signaling, and cytotoxicity of these LDCs to CXCR2 expressing myeloid cells. Our data suggests that our engineered proteins are superior binders and activators of CXCR2 axis signaling compared to WT CXCR2 ligands. Utilizing CXCR2 knockin models we demonstrated that the cytotoxicity of our LDCs is CXCR2 dependent. In vivo, we are utilizing the KPC (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) mouse model of PDAC, which we've shown in preliminary studies to, like human PDAC, support an abundance of MDSCs in tumors as well as secondary lymphoid organs such as the spleen. We anticipate that this study will demonstrate the therapeutic potential and actionability of targeting MDSCs and will provide novel biotherapeutic drug candidates that will ultimately improve immunotherapy outcomes in patients with PDAC. Citation Format: Benjamin N. Christopher, Lety Reyes, Reeder Robinson, Lena Golick, Nathan Dolloff. Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A031.

Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer.

New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor site. T cells infused into the bladder directly encounter immunosuppressive populations, such as myeloid derived suppressor cells (MDSCs), that can attenuate T cell responses. Intravesical instillation of gemcitabine can be used as a lymphodepleting agent to precondition the bladder microenvironment for infused T cell products. Urine samples from bladder cancer patients and healthy donors were analyzed by flow cytometry and cytometric bead array for immune profiling and cytokine quantification. MDSCs were isolated from the urine and cocultured with stimulated T cells to assess effects on proliferation. An orthotopic murine model of bladder cancer was established using the MB49-OVA cell line and immune profiling was performed. MDSCs from tumor-bearing mice were cocultured with OT-I splenocytes to assess T cell proliferation. Mice received intravesical instillation of gemcitabine and depletion of immune cells was measured via flow cytometry. Bladder tumor growth of mice treated with intravesical gemcitabine, OT-I transgenic T cells, or combination was monitored via ultrasound measurement. In comparison to healthy donors, urine specimen from bladder cancer patients show high levels of MDSCs and cytokines associated with myeloid chemotaxis, T cell chemotaxis, and inflammation. T cells isolated from healthy donors were less proliferative when cocultured with MDSCs from the urine. Orthotopic murine bladder tumors also presented with high levels of MDSCs along with enrichment of cytokines found in the patient urine samples. MDSCs isolated from spleens of tumor-bearing mice exerted suppressive effects on the proliferation of OT-I T cells. Intravesical instillation of gemcitabine reduced overall immune cells, MDSCs, and T cells in orthotopic bladder tumors. Combination treatment with gemcitabine and OT-I T cells resulted in sustained anti-tumor responses in comparison to monotherapy treatments. MDSCs are enriched within the microenvironment of bladder tumors and are suppressive to T cells. Gemcitabine can be used to lymphodeplete bladder tumors and precondition the microenvironment for intravesical ACT.

CUL4B functions as a tumor suppressor in KRAS-driven lung tumors by inhibiting the recruitment of myeloid-derived suppressor cells.

Lung cancer is the leading cause of cancer-related death worldwide. KRAS mutations are the most common oncogenic alterations found in lung cancer. Unfortunately, treating KRAS-mutant lung adenocarcinoma (ADC) remains a major oncotherapeutic challenge. Here, we used both autochthonous and transplantable KRAS-mutant tumor models to investigate the role of tumor-derived CUL4B in KRAS-driven lung cancers. We showed that knockout or knockdown of CUL4B promotes lung ADC growth and progression in both models. Mechanistically, CUL4B directly binds to the promoter of Cxcl2 and epigenetically represses its transcription. CUL4B deletion increases the expression of CXCL2, which binds to CXCR2 on myeloid-derived suppressor cells (MDSCs) and promotes their migration to the tumor microenvironment. Targeting of MDSCs significantly delayed the growth of CUL4B knockdown KRAS-mutant tumors. Collectively, our study provides mechanistic insights into the novel tumor suppressor-like functions of CUL4B in regulating KRAS-driven lung tumor development.

Epigenetic targeting of myeloid-derived suppressor cells: time to move into infectious diseases?

Epigenetic targeting of myeloid-derived suppressor cells: time to move into infectious diseases?

Janus Silica Nanoparticle-Based Tumor Microenvironment Modulator for Restoring Tumor Sensitivity to Programmed Cell Death Ligand 1 Immune Checkpoint Blockade Therapy.

An immunosuppressive tumor microenvironment (TME) with inadequate and exhausted tumor-infiltrating cytotoxic lymphocytes and abundant cellular immunosuppressors is the major obstacle responsible for the poor efficacy of PD-1/PD-L1 (programmed cell death 1 and its ligand 1) immune checkpoint blockade (ICB) therapy. Herein, a Janus silica nanoparticle (JSNP)-based immunomodulator is explored to reshape the TME for boosting the therapeutic outcomes of αPD-L1 therapy. The designed JSNP has two distinct domains, namely, an ultra pH-responsive side (UPS), which could encapsulate PI3Kγ inhibitor IPI549 in the pore structure, and a polycation-grafted intra-glutathione (GSH)-sensitive side (IGS), which could absorb CXCL9 cDNA on the surface. The final IPI549@UPS-IGS-PDMAEMA@CXCL9 cDNA (IUIPC) could release IPI549 in weak acid TME to target myeloid-derived suppressor cells (MDSCs) to reverse negative immunoregulation and then release CXCL9 cDNA in tumor cells with abundant GSH for sustained CXCL9 chemokine expression and secretion to improve cytotoxic lymphocyte recruitment signals, thereby jointly restoring tumor sensitivity to PD-1/PD-L1 ICB therapy. As expected, the IUIPC-mediated TME remodeling during αPD-L1 therapy significantly ameliorated TME immunosuppression, as well as induced potent systemic antitumor immune responses, which ultimately achieved a robustly boosted antitumor efficacy proven by remarkable suppression of primary tumor growth, obvious prevention of tumor recurrence, and significant regression of abscopal tumors. Hence, the IUIPC-mediated TME-regulating strategy provides an enormous perspective for the improvement of PD-1/PD-L1 ICB therapy.

Single-cell transcriptome analysis reveals the clinical implications of myeloid-derived suppressor cells in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSC) is the most common malignant tumor that arises in the epithelium of the head and neck regions. Myeloid-derived suppressor cells (MDSCs) are one of the tumor-infiltrating immune cell populations, which play a powerful role in inhibiting anti-tumor immune response. Herein, we employed a single-cell RNA sequencing (scRNA-seq) dataset to dissect the heterogeneity of myeloid cells. We found that SPP1 + tumor-associated macrophages (TAMs) and MDSCs were the most abundant myeloid cells in the microenvironment. By cell cluster deconvolution from bulk RNA-seq datasets of larger patient groups, we observed that highly-infiltrated MDSC was a poor prognostic marker for patients' overall survival (OS) probabilities. To better apply the MDSC OS prediction values, we identified a set of six MDSC-related genes (ALDOA, CD52, FTH1, RTN4, SLC2A3, and TNFAIP6) as the prognostic signature. In both training and test cohorts, MDSC-related prognostic signature showed a promising value for predicting patients' prognosis outcomes. Further parsing the ligand-receptor pairs of intercellular communications by CellChat, we found that MDSCs could frequently interact with cytotoxic CD8 + T cells, SPP1 + TAMs, and endothelial cells. These interactions likely contributed to the establishment of an immunosuppressive microenvironment and the promotion of tumor angiogenesis. Our findings suggest that targeting MDSCs may serve as an alternative and promising target for the immunotherapy of HNSC.

Enhancing immunotherapy response in melanoma: myeloid-derived suppressor cells as a therapeutic target.

Despite the remarkable success of immune checkpoint inhibitors (ICIs) in melanoma treatment, resistance to them remains a substantial clinical challenge. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that can suppress antitumor immune responses mediated by T and natural killer cells and promote tumor growth. They are major contributors to ICI resistance and play a crucial role in creating an immunosuppressive tumor microenvironment. Therefore, targeting MDSCs is considered a promising strategy to improve the therapeutic efficacy of ICIs. This Review describes the mechanism of MDSC-mediated immune suppression, preclinical and clinical studies on MDSC targeting, and potential strategies for inhibiting MDSC functions to improve melanoma immunotherapy.

Augmenting Immunogenic Cell Death and Alleviating Myeloid-Derived Suppressor Cells by Sono-Activatable Semiconducting Polymer Nanopartners for Immunotherapy.

Inducing immunogenic cell death (ICD) by sonodynamic therapy (SDT) is promising for cancer immunotherapy, which however is inefficient due to oxygen depletion that compromises SDT effect and mediates recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs). The fabrication of sono-activatable semiconducting polymer nanopartners (SPNTi ) to simultaneously augment ICD and alleviate MDSCs for immunotherapy is reported. A sonodynamic semiconducting polymer, hydrophobic hypoxia-responsive tirapazamine (TPZ)-conjugate, and MDSC-targeting drug (ibrutinib) are encapsulated inside such SPNTi with surface shell of a singlet oxygen (1 O2 )-cleavable amphiphilic polymer. TPZ and ibrutinib serve as drug partners to enlarge immunotherapeutic effect. Upon sono-activation, SPNTi generate 1 O2 to break 1 O2 -cleavable polymers for in-situ liberations of TPZ-conjugate and ibrutinib in tumor sites, and oxygen is consumed to create severer hypoxic tumor microenvironment, in which, TPZ-conjugate is activated for augmenting ICD action, while ibrutinib alleviates MDSCs for promoting antitumor immunological effect. In a bilateral tumor mouse model, SPNTi -mediated sono-activatable immunotherapy results in growth restraints of primary and distant tumors and noteworthy precaution of tumor metastases. This study thus provides a sono-activatable immunotherapeutic strategy with high precision and safety for cancer via overcoming post-treatment hypoxia and targeting MDSCs. This article is protected by copyright. All rights reserved.

THU-345 - Targeting myeloid-derived suppressor cells in a carbon tetrachloride-induced murine model of chronic liver injury

THU-345 - Targeting myeloid-derived suppressor cells in a carbon tetrachloride-induced murine model of chronic liver injury

Effect of MDSC-targeted TFF2-MSA with PD-1 blockade therapy in advanced gastric cancer models.

e16037 Background: Recent studies revealed chemotherapy increases anti-PD1 response of gastric cancer (GC) by reducing myeloid-derived suppressor cells (MDSCs). However, a more specific MDSC-targeted treatment is needed to further improve anti-PD1 efficacy in advanced GC. Trefoil factor family 2 (TFF2), a partial agonist of CXCR4 and a secreted anti-inflammatory peptide, can suppress MDSC expansion. Here, we developed a novel MDSC-targeted peptide TFF2-MSA and investigated whether it can synergize with anti-PD1 in syngeneic GC mouse models. Methods: Murine serum albumin (MSA) was fused to murine TFF2 to generate TFF2-MSA peptide with an extended serum half-life. ACKP (Atp4b-Cre; Cdh1-/-; LSL-KrasG12D; Trp53-/-) GC cells developed from a highly malignant diffuse GC mouse model were grafted subcutaneously into HDC-GFP transgenic mice in which the immunosuppressive histidine decarboxylase (HDC)-expressing myeloid cells were traced with GFP. These recipient mice then received either TFF2-MSA or anti-PD-1 antibody or both when tumors reached 150 mm3. At the endpoint, flow cytometry analysis was performed to examine immune profiles. In parallel, a group of the s.c. tumor bearing mice were followed up for survival differences in response to the treatments. In the orthotopic model, ACKP-luc cells were implanted to stomach submucosa, and recipient mice received the same treatments started after 1 week. In the metastasis model, subcutaneous flank tumors were resected in ACKP-grafted mice once tumors reached 500 mm3 to permit spontaneous lung metastasis, and mice then received the same treatments. Results: While either TFF2-MSA or PD-1 antibody showed little benefit as a single agent (TGI 15% and 25% respectively, p>0.05), their combination dramatically suppressed ACKP s.c. tumor growth (TGI 78%, p<0.0001) and markedly prolonged median survival (64 days vs. 32.5 days in control) in a synergistic manner. The combination therapy efficiently reduced tumor HDC-GFP+ MDSCs by 67%, and profoundly increased tumor-infiltrating cytotoxic CD8+ T cells by 18 fold. The myeloid/lymphoid progenitor and output ratio in the bone marrow were decreased by the combination, to a similar level of tumor-free mice. While standard chemotherapy (5-fluorouracil and oxaliplatin) showed no efficacy, adding chemotherapy to the combination further improved treatment efficacy (TGI 91%) and extended median survival to 73 days. In addition, in the orthotopic model, the TFF2-MSA/PD-1 antibody combination eradicated GC in 80% mice without recurrence compared to 0% with either monotherapy. Finally, the combination of TFF2-MSA/PD-1 antibody significantly reduced 80% lung metastasis (vs. control, p<0.0001), compared to minimal inhibition with either monotherapy (p>0.05). Conclusions: Targeting MDSCs using TFF2-MSA synergizes with PD-1 blockade therapy in advanced and metastatic syngeneic mouse models of gastric cancer.

Myeloid-derived suppressor cells deficient in cholesterol biosynthesis promote tumor immune evasion

Cancer immunotherapy targeting myeloid-derived suppressor cells (MDSCs) is one of the most promising anticancer strategies. Metabolic reprogramming is vital for MDSC activation, however, the regulatory mechanisms of cholesterol metabolic reprogramming in MDSCs remains largely unexplored. Using the receptor-interacting protein kinase 3 (RIPK3)-deficient MDSC model, a previously established tumor-infiltrating MDSC-like model, we found that the cholesterol accumulation was significantly decreased in these cells. Moreover, the phosphorylated AKT-mTORC1 signaling was reduced, and downstream SREBP2-HMGCR-mediated cholesterol synthesis was blunted. Interestingly, cholesterol deficiency profoundly elevated the immunosuppressive activity of MDSCs. Mechanistically, cholesterol elimination induced nuclear accumulation of LXRβ, thereby promoting LXRβ-RXRα heterodimer binding of a novel composite element in the promoter of Arg1. Furthermore, itraconazole enhanced the immunosuppressive activity of MDSCs to boost tumor growth by suppressing the RIPK3-AKT-mTORC1 pathway and impeding cholesterol synthesis. Our findings demonstrate that RIPK3 deficiency leads to cholesterol abrogation in MDSCs, which facilitates tumor-infiltrating MDSC activation, and highlight the therapeutic potential of targeting cholesterol synthesis to overcome tumor immune evasion.

The adaptor protein TRAF3 is an immune checkpoint that inhibits myeloid-derived suppressor cell expansion.

Myeloid-derived suppressor cells (MDSCs) are aberrantly expanded in cancer patients and under other pathological conditions. These cells orchestrate the immunosuppressive and inflammatory network to facilitate cancer metastasis and mediate patient resistance to therapies, and thus are recognized as a prime therapeutic target of human cancers. Here we report the identification of the adaptor protein TRAF3 as a novel immune checkpoint that critically restrains MDSC expansion. We found that myeloid cell-specific Traf3-deficient (M-Traf3 -/-) mice exhibited MDSC hyperexpansion during chronic inflammation. Interestingly, MDSC hyperexpansion in M-Traf3 -/- mice led to accelerated growth and metastasis of transplanted tumors associated with an altered phenotype of T cells and NK cells. Using mixed bone marrow chimeras, we demonstrated that TRAF3 inhibited MDSC expansion via both cell-intrinsic and cell-extrinsic mechanisms. Furthermore, we elucidated a GM-CSF-STAT3-TRAF3-PTP1B signaling axis in MDSCs and a novel TLR4-TRAF3-CCL22-CCR4-G-CSF axis acting in inflammatory macrophages and monocytes that coordinately control MDSC expansion during chronic inflammation. Taken together, our findings provide novel insights into the complex regulatory mechanisms of MDSC expansion and open up unique perspectives for the design of new therapeutic strategies that aim to target MDSCs in cancer patients.

Targeting myeloid-derived suppressor cells in combination with tumor cell vaccination predicts anti-tumor immunity and breast cancer dormancy: an in silico experiment

Among the different breast cancer subsets, triple-negative breast cancer (TNBC) has the worst prognosis and limited options for targeted therapies. Immunotherapies are emerging as novel treatment opportunities for TNBC. However, the surging immune response elicited by immunotherapies to eradicate cancer cells can select resistant cancer cells, which may result in immune escape and tumor evolution and progression. Alternatively, maintaining the equilibrium phase of the immune response may be advantageous for keeping a long-term immune response in the presence of a small-size residual tumor. Myeloid-derived suppressor cells (MDSCs) are activated, expanded, and recruited to the tumor microenvironment by tumor-derived signals and can shape a pro-tumorigenic micro-environment by suppressing the innate and adaptive anti-tumor immune responses. We recently proposed a model describing immune-mediated breast cancer dormancy instigated by a vaccine consisting of dormant, immunogenic breast cancer cells derived from the murine 4T1 TNBC-like cell line. Strikingly, these 4T1-derived dormant cells recruited fewer MDSCs compared to aggressive 4T1 cells. Recent experimental studies demonstrated that inactivating MDSCs has a profound impact on reconstituting immune surveillance against the tumor. Here, we developed a deterministic mathematical model for simulating MDSCs depletion from mice bearing aggressive 4T1 tumors resulting in immunomodulation. Our computational simulations indicate that a vaccination strategy with a small number of tumor cells in combination with MDSC depletion can elicit an effective immune response suppressing the growth of a subsequent challenge with aggressive tumor cells, resulting in sustained tumor dormancy. The results predict a novel therapeutic opportunity based on the induction of effective anti-tumor immunity and tumor dormancy.

Modulation of T-cell function by myeloid-derived suppressor cells in hematological malignancies.

Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes that negatively regulate the immune response to cancer and chronic infections. Abnormal myelopoiesis and pathological activation of myeloid cells generate this heterogeneous population of myeloid-derived suppressor cells. They are characterized by their distinct transcription, phenotypic, biochemical, and functional features. In the tumor microenvironment (TME), myeloid-derived suppressor cells represent an important class of immunosuppressive cells that correlate with tumor burden, stage, and a poor prognosis. Myeloid-derived suppressor cells exert a strong immunosuppressive effect on T-cells (and a broad range of other immune cells), by blocking lymphocyte homing, increasing production of reactive oxygen and nitrogen species, promoting secretion of various cytokines, chemokines, and immune regulatory molecules, stimulation of other immunosuppressive cells, depletion of various metabolites, and upregulation of immune checkpoint molecules. Additionally, the heterogeneity of myeloid-derived suppressor cells in cancer makes their identification challenging. Overall, they serve as a major obstacle for many cancer immunotherapies and targeting them could be a favorable strategy to improve the effectiveness of immunotherapeutic interventions. However, in hematological malignancies, particularly B-cell malignancies, the clinical outcomes of targeting these myeloid-derived suppressor cells is a field that is still to be explored. This review summarizes the complex biology of myeloid-derived suppressor cells with an emphasis on the immunosuppressive pathways used by myeloid-derived suppressor cells to modulate T-cell function in hematological malignancies. In addition, we describe the challenges, therapeutic strategies, and clinical relevance of targeting myeloid-derived suppressor cells in these diseases.