Targeting CSF1R in myeloid-derived suppressor cells: insights into its immunomodulatory functions in colorectal cancer and therapeutic implications.

OBJECTIVE: This study aimed to investigate the critical role of MDSCs in CRC immune suppression, focusing on the CSF1R and JAK/STAT3 signaling axis. Additionally, it assessed the therapeutic efficacy of LNCs@CSF1R siRNA and anti-PD-1 in combination. METHODS: Single-cell transcriptome sequencing data from CRC and adjacent normal tissues identified MDSC-related differentially expressed genes. RNA-seq analysis comprehensively profiled MDSC gene expression in murine CRC tumors. LNCs@CSF1R siRNA nanocarriers effectively targeted and inhibited CSF1R. Flow cytometry quantified changes in MDSC surface markers post-CSF1R inhibition. RNA-seq and pathway enrichment analyses revealed the impact of CSF1R on MDSC metabolism and signaling. The effect of CSF1R inhibition on the JAK/STAT3 signaling axis was validated using Colivelin and metabolic assessments. Glucose and fatty acid uptake were measured via fluorescence-based flow cytometry. The efficacy of LNCs@CSF1R siRNA and anti-PD-1, alone and in combination, was evaluated in a murine CRC model with extensive tumor section analyses. RESULTS: CSF1R played a significant role in MDSC-mediated immune suppression. LNCs@CSF1R siRNA nanocarriers effectively targeted MDSCs and inhibited CSF1R. CSF1R regulated MDSC fatty acid metabolism and immune suppression through the JAK/STAT3 signaling axis. Inhibition of CSF1R reduced STAT3 activation and target gene expression, which was rescued by Colivelin. Combined treatment with LNCs@CSF1R siRNA and anti-PD-1 significantly slowed tumor growth and reduced MDSC abundance within CRC tumors. CONCLUSION: CSF1R via the JAK/STAT3 axis critically regulates MDSCs, particularly in fatty acid metabolism and immune suppression. Combined therapy with LNCs@CSF1R siRNA and anti-PD-1 enhances therapeutic efficacy in a murine CRC model, providing a strong foundation for future clinical applications.

The effect of exercise and disease status on mobilization of anti-tumorigenic and pro-tumorigenic immune cells in women with breast cancer.

Background: Mobilization of certain immune cells may improve the ability of the immune system to combat tumor cells, but the effect of acute exercise on mobilizing immune cells has been sparsely investigated in cancer patients. Therefore, we examined how acute exercise influences circulating immune cells in breast cancer patients. Methods: Nineteen newly diagnosed breast cancer patients aged 36-68 performed 30 minutes of moderate-intensity exercise with a cycle ergometer. Blood samples were collected at various time points: at rest, at 15 (E15) and 30 minutes (E30) after onset of the exercise, and at 30 and 60 minutes post-exercise. We analyzed several immune cell subsets using flow cytometry. Results: Acute exercise increased the number of total leukocytes, neutrophils, lymphocytes, monocytes, basophils, total T-cells, CD4+ T-cells, T helper (Th) 2-cells, Th 17-cells, CD8+ T-cells, CD4-CD8- T-cells, CD56+ natural killer (NK) cells, and CD14-CD16+ monocytes. Many of the changes were transient. Proportions of NK-cells and CD8+ T-cells increased, while the proportion of myeloid derived suppressor cells (MDSCs) reduced, and proportion of regulatory T-cells remained unchanged by exercise. Several associations were detected between cell mobilizations and disease state. For instance, tumor size correlated negatively with NK cell mobilization at E15, and progesterone receptor positivity correlated negatively with CD8+ T-cell mobilization. Conclusion: The findings show that the proportions of CD8+ T-cells and NK cells increased and the proportion of MDSCs proportion decreased in breast cancer patients after 30-minute exercise, suggesting a change in the profile of circulating immune cells towards more cytotoxic/anti-tumorigenic. The mobilization of some immune cells also appears to be related to the disease state.

Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a potentially lethal disease lacking effective treatments. Its immunosuppressive tumor microenvironment (TME) allows it to evade host immunosurveillance and limits response to immunotherapy. Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells is required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an antitumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells, and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the therapeutic potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.

Myeloid-derived suppressor cells-induced exhaustion of CD8 + T-cell participates in rejection after liver transplantation.

Liver transplantation (LT) rejection remains the most pervasive problem associated with this procedure, while the mechanism involved is still complicated and undefined. One promising solution may involve the use of myeloid-derived suppressor cells (MDSC). However, the immunological mechanisms underlying the effects of MDSC after LT remain unclear. This study is meant to clarify the role MDSCs play after liver transplantation. In this study, we collected liver tissue and peripheral blood mononuclear cells (PBMC) from LT patients showing varying degrees of rejection, as well as liver and spleen tissue samples from mice LT models. These samples were then analyzed using flow cytometry, immunohistochemistry and multiple immunofluorescence. M-MDSCs and CD8 + T-cells extracted from C57/BL6 mice were enriched and cocultured for in vitro experiments. Results, as obtained in both LT patients and LT mice model, revealed that the proportion and frequency of M-MDSC and PD-1 + T-cells increased significantly under conditions associated with a high degree of LT rejection. Within the LT rejection group, our immunofluorescence results showed that a close spatial contiguity was present between PD-1 + T-cells and M-MDSCs in these liver tissue samples and the proportion of CD84/PD-L1 double-positive M-MDSC was greater than that of G-MDSC. There was a positive correlation between the activity of CD84 and immunosuppressive function of M-MDSCs including PD-L1 expression and reactive oxygen species (ROS) production, as demonstrated in our in vitro model. M-MDSCs treated with CD84 protein were able to induce co-cultured CD8 + T-cells to express high levels of exhaustion markers. We found that CD84 regulated M-MDSC function via expression of PD-L1 through activation of the Akt/Stat3 pathway. These results suggest that the capacity for CD84 to regulate M-MDSC induction of CD8 + T-cell exhaustion may play a key role in LT rejection. Such findings provide important, new insights into the mechanisms of tolerance induction in LT.

Effects of the subtypes of apolipoprotein E on immune inhibition and prognosis in patients with Hepatocellular Carcinoma.

PURPOSE: To investigate whether prognosis of patients with hepatocellular carcinoma (HCC) is affected by the abundance and subgroups of myeloid-derived suppressor cells (MDSCs) as well as subtypes and expression of apolipoprotein E (apoE). METHODS: 31 HCC patients were divided into three groups according to blood total apoE level for detecting the abundance of immunoregulatory cells by flow cytometry. Tumour tissue microarrays from 360 HCC patients were evaluated about the abundance and subgroups of MDSCs and the expression of apoE2, apoE3, apoE4 by immunofluorescence staining and immunohistochemistry staining. Survival analysis by means of univariate, multivariate COX regression and Kaplan-Meier methods of the 360 patients was performed based on clinical and pathological examinations along with 10 years' follow-up data. RESULTS: The lower apoE group presented higher abundance of MDSCs in the peripheral blood of HCC patients than higher apoE group. The abundance of monocyte-like MDSCs (M-MDSCs) was higher in the apoE low level group than high level group (p = 0.0399). Lower H-score of apoE2 (HR = 6.140, p = 0.00005) and higher H-score of apoE4 (HR = 7.001, p = 0.009) in tumour tissue were significantly associated with shorter overall survival (OS). The higher infiltration of polymorphonuclear granulocyte-like MDSCs (PMN-MDSCs, HR = 3.762, p = 0.000009) and smaller proportion of M-MDSCs of total cells (HR = 0.454, p = 0.006) in tumour tissue were independent risk factors for shorter recurrence-free survival (RFS). CONCLUSION: The abundance of MDSCs in HCC patients' plasma negatively correlates with the level of apoE. The expression of apoE4 in HCC tissue indicated a poor prognosis while apoE2 might be a potential protective factor.

Generation of Myeloid-Derived Suppressor Cells Mediated by MicroRNA-125a-5p in Melanoma.

The ability of tumor-derived extracellular vesicles (EVs) to modulate the function of myeloid cells is widely recognized. Hence, a comprehensive understanding of the distinct components associated with EVs and the signals that they deliver to myeloid cells could provide potential approaches to impede the immunosuppression by myeloid-derived suppressor cells (MDSCs). We investigated melanoma EV-associated microRNAs (miRs) using the RET transgenic melanoma mouse model and simulated their transfer to normal myeloid cells by transfecting immature mouse myeloid cells and human monocytes. We observed elevated levels of miR-125a-5p, -125b-5p, and let-7e-5p in mouse melanoma-infiltrating MDSCs. In addition, miR-125a-5p levels in the tumor microenvironment correlated with mouse melanoma progression. The delivery of miR-125a-5p, alone or in combination with let-7e-5p and miR-99b-5p from the same genomic cluster, to normal myeloid cells resulted in their conversion to MDSC-like cells. Our findings indicate that miR-125a-5p could modulate myeloid cell activation in the melanoma microenvironment via a NF-κB-dependent mechanism.

Tumour Microenvironment: The General Principles of Pathogenesis and Implications in Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide, constituting around 30-40% of all cases. Almost 60% of patients develop relapse of refractory DLBCL. Among the reasons for the therapy failure, tumour microenvironment (TME) components could be involved, including tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (TANs), cancer-associated fibroblasts (CAFs), and different subtypes of cytotoxic CD8+ cells and T regulatory cells, which show complex interactions with tumour cells. Understanding of the TME can provide new therapeutic options for patients with DLBCL and improve their prognosis and overall survival. This review provides essentials of the latest understanding of tumour microenvironment elements and discusses their role in tumour progression and immune suppression mechanisms which result in poor prognosis for patients with DLBCL. In addition, we point out important markers for the diagnostic purposes and highlight novel therapeutic targets.

Comprehensive approach to cancer immunotherapy - Simultaneous targeting of myeloid-derived suppressor cells and cancer cells with AFP conjugates.

The immune system plays a pivotal role in combating diseases, including cancer, with monocytes emerging as key regulators of immune response dynamics. This article describes a novel strategy for cancer treatment centered on depleting myeloid-derived suppressor cells (MDSCs), to enhance the overall immune response while simultaneously targeting cancer cells directly. Alpha-fetoprotein (AFP) is an oncofetal protein that plays an important role in delivering nutrients to immature monocytes, embryonic, and cancer cells in a targeted manner. AFP can be repurposed, making it a vehicle for delivering toxins, rather than nutrients to kill cancer cells and deplete MDSCs in the tumor microenvironment (TME). Depleting monocytes not only stimulates the immune system but also improves the lymphocyte-to-monocyte ratio (LMR), often low in cancer patients. AFP combined with cytotoxic drugs, offers dual benefit-immune stimulation and targeted chemotherapy. Studies in xenograft models demonstrated high efficacy and safety of AFP-toxin conjugates, surpassing conventional targeted chemotherapy. Such conjugates have also been reported to provide superior efficacy and safety in cancer patients compared to chemotherapy. This approach, using AFP conjugated with toxins, either covalently or non-covalently, presents a safe and highly effective option for cancer immuno/chemotherapy.

Engineered CD147-Deficient THP-1 Impairs Monocytic Myeloid-Derived Suppressor Cell Differentiation but Maintains Antibody-Dependent Cellular Phagocytosis Function for Jurkat T-ALL Cells with Humanized Anti-CD147 Antibody.

CD147 is upregulated in cancers, including aggressive T-ALL. Traditional treatments for T-ALL often entail severe side effects and the risk of relapse, highlighting the need for more efficacious therapies. ADCP contributes to the antitumor response by enhancing the ability of phagocytic cells to engulf cancer cells upon antibody binding. We aimed to engineer CD147KO THP-1 cells and evaluated their differentiation properties compared to the wild type. A humanized anti-CD147 antibody, HuM6-1B9, was also constructed for investing the phagocytic function of CD147KO THP-1 cells mediated by HuM6-1B9 in the phagocytosis of Jurkat T cells. The CD147KO THP-1 was generated by CRISPR/Cas9 and maintained polarization profiles. HuM6-1B9 was produced in CHO-K1 cells and effectively bound to CD147 with high binding affinity (KD: 2.05 ± 0.30 × 10-9 M). Additionally, HuM6-1B9 enhanced the phagocytosis of Jurkat T cells by CD147KO THP-1-derived LPS-activated macrophages (M-LPS), without self-ADCP. The formation of THP-1-derived mMDSC was limited in CD147KO THP-1 cells, highlighting the significant impact of CD147 deletion. Maintaining expression markers and phagocytic function in CD147KO THP-1 macrophages supports future engineering and the application of induced pluripotent stem cell-derived macrophages. The combination of HuM6-1B9 and CD147KO monocyte-derived macrophages holds promise as an alternative strategy for T-ALL.

Inhibition of non-small cell lung cancer metastasis by knocking down APE1 through regulating myeloid-derived suppressor cells-induced immune disorders.

BACKGROUND: Non-small cell lung cancer (NSCLC) represents a highly immunogenic malignancy. Immunologic tolerance facilitated by myeloid-derived suppressor cells (MDSCs) is implicated in primary or secondary resistance mechanisms in NSCLC. The potential role of APE1 in regulating NSCLC metastasis by targeting MDSCs remains uncertain. METHODS: This study utilized a plasmid, Plxpsp-mGM-CSF, to induce elevated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in A549 cells. Tumor transplantation experiments involved A549, A549+GM-CSF, and A549+GM-CSF-siAPE1 cell lines. Evaluation encompassed MDSCs, Treg cells, IgG, CD3, and CD8 levels. RESULTS: Notably, lung cancer tissues and cells displayed markedly reduced APE1 expression. siAPE1 transfection significantly curtailed tumor growth compared to the A549+GM-CSF group. APE1 knockdown orchestrated immune system modulation in lung tumor mice, characterized by diminished MDSCs but augmented Treg cells, IgG, CD3, and CD8. Additionally, APE1 knockdown led to reduced levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12) and a concurrent upregulation of the anti-MDSC cytokine IL-1ra. Furthermore, APE1 knockdown impeded cell viability in both A549 and H1650 cells. CONCLUSIONS: Transplantation of A549-GM-CSF amplified MDSC levels, fostering accelerated tumor growth, while mitigating MDSC levels through APE1 knockdown hindered tumor progression and alleviated inflammatory infiltration in lung cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach for lung cancer prevention and treatment, presenting novel insights for NSCLC management.

Cannabidiol alleviates suture-induced corneal pathological angiogenesis and inflammation by inducing myeloid-derived suppressor cells.

BACKGROUND: Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to investigate the anti-angiogenic and anti-inflammatory effects of cannabidiol and its mechanism of action. METHOD: An in vivo corneal neovascularization (CNV) model was established using the suture method to investigate the inhibitory effects of CBD on suture-induced corneal inflammation, pathological blood vessel formation, and lymphangiogenesis. Additionally, the impact of CBD on immune cells was studied. In vitro methodologies, including cell sorting and co-culture, were employed to elucidate its mechanism of action. RESULTS: Compared with the CNV group, CBD can inhibit CNV, lymphangiogenesis, and inflammation induced via the suture method. In addition, CBD specifically induced CD45+CD11b+Gr-1+ cell upregulation, which significantly inhibited the proliferation of CD4+ T lymphocytes in vitro and exhibited a CD31+ phenotype, proving that they were myeloid-derived suppressor cells (MDSCs). We administered anti-Gr-1 to mice to eliminate MDSCs in vivo and found that anti-Gr-1 partially reversed the anti-inflammatory and angiogenic effects of CBD. Furthermore, we found that compared with MDSCs in the normal group, CBD-induced MDSCs overexpress peroxisome proliferator-activated receptor-gamma (PPAR-γ). Administering PPAR-γ inhibitor in mice almost reversed the induction of MDSCs by CBD, demonstrating the role of PPAR-γ in the function of CBD. CONCLUSION: This study indicates that CBD may induce MDSCs upregulation by activating the nuclear receptor PPAR-γ, exerting anti-inflammatory, antiangiogenic, and lymphangiogenic effects, and revealing potential therapeutic targets for corneal neovascularization and lymphangiogenesis.

Myeloid-derived suppressor cells in peripheral blood as predictive biomarkers in patients with solid tumors undergoing immune checkpoint therapy: systematic review and meta-analysis.

Background: Immunotherapeutic approaches, including immune checkpoint inhibitor (ICI) therapy, are increasingly recognized for their potential. Despite notable successes, patient responses to these treatments vary significantly. The absence of reliable predictive and prognostic biomarkers hampers the ability to foresee outcomes. This meta-analysis aims to evaluate the predictive significance of circulating myeloid-derived suppressor cells (MDSC) in patients with solid tumors undergoing ICI therapy, focusing on progression-free survival (PFS) and overall survival (OS). Methods: A comprehensive literature search was performed across PubMed and EMBASE from January 2007 to November 2023, utilizing keywords related to MDSC and ICI. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) directly from the publications or calculated them based on the reported data. A hazard ratio greater than 1 indicated a beneficial effect of low MDSC levels. We assessed heterogeneity and effect size through subgroup analyses. Results: Our search yielded 4,023 articles, of which 17 studies involving 1,035 patients were included. The analysis revealed that patients with lower levels of circulating MDSC experienced significantly improved OS (HR=2.13 [95% CI 1.51-2.99]) and PFS (HR=1.87 [95% CI 1.29-2.72]) in response to ICI therapy. Notably, heterogeneity across these outcomes was primarily attributed to differences in polymorphonuclear MDSC (PMN-MDSC) subpopulations and varying cutoff methodologies used in the studies. The monocytic MDSC (M-MDSC) subpopulation emerged as a consistent and significant prognostic marker across various subgroup analyses, including ethnicity, tumor type, ICI target, sample size, and cutoff methodology. Conclusions: Our findings suggest that standardized assessment of MDSC, particularly M-MDSC, should be integral to ICI therapy strategies. These cells hold the promise of identifying patients at risk of poor response to ICI therapy, enabling tailored treatment approaches. Further research focusing on the standardization of markers and validation of cutoff methods is crucial for integrating MDSC into clinical practice. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023420095, identifier CRD42023420095.

Harnessing Metformin's Immunomodulatory Effects on Immune Cells to Combat Breast Cancer.

Metformin, a medication known for its anti-glycemic properties, also demonstrates potent immune system activation. In our study, using a 4T1 breast cancer model in BALB/C WT mice, we examined metformin's impact on the functional phenotype of multiple immune cells, with a specific emphasis on natural killer T (NKT) cells due to their understudied role in this context. Metformin administration delayed the appearance and growth of carcinoma. Furthermore, metformin increased the percentage of IFN-γ+ NKT cells, and enhanced CD107a expression, as measured by MFI, while decreasing PD-1+, FoxP3+, and IL-10+ NKT cells in spleens of metformin-treated mice. In primary tumors, metformin increased the percentage of NKp46+ NKT cells and increased FasL expression, while lowering the percentages of FoxP3+, PD-1+, and IL-10-producing NKT cells and KLRG1 expression. Activation markers increased, and immunosuppressive markers declined in T cells from both the spleen and tumors. Furthermore, metformin decreased IL-10+ and FoxP3+ Tregs, along with Gr-1+ myeloid-derived suppressor cells (MDSCs) in spleens, and in tumor tissue, it decreased IL-10+ and FoxP3+ Tregs, Gr-1+, NF-κB+, and iNOS+ MDSCs, and iNOS+ dendritic cells (DCs), while increasing the DCs quantity. Additionally, increased expression levels of MIP1a, STAT4, and NFAT in splenocytes were found. These comprehensive findings illustrate metformin's broad immunomodulatory impact across a variety of immune cells, including stimulating NKT cells and T cells, while inhibiting Tregs and MDSCs. This dynamic modulation may potentiate its use in cancer immunotherapy, highlighting its potential to modulate the tumor microenvironment across a spectrum of immune cell types.

Single-cell transcriptomic analysis reveals heterogeneous features of myeloid-derived suppressor cells in newborns.

The transitory emergence of myeloid-derived suppressor cells (MDSCs) in infants is important for the homeostasis of the immune system in early life. The composition and functional heterogeneity of MDSCs in newborns remain elusive, hampering the understanding of the importance of MDSCs in neonates. In this study, we unraveled the maturation trajectory of polymorphonuclear (PMN)-MDSCs from the peripheral blood of human newborns by performing single-cell RNA sequencing. Results indicated that neonatal PMN-MDSCs differentiated from self-renewal progenitors, antimicrobial PMN-MDSCs, and immunosuppressive PMN-MDSCs to late PMN-MDSCs with reduced antimicrobial capacity. We also established a simple framework to distinguish these distinct stages by CD177 and CXCR2. Importantly, preterm newborns displayed a reduced abundance of classical PMN-MDSCs but increased late PMN-MDSCs, consistent with their higher susceptibility to infections and inflammation. Furthermore, newborn PMN-MDSCs were distinct from those from cancer patients, which displayed minimum expression of genes about antimicrobial capacity. This study indicates that the heterogeneity of PMN-MDSCs is associated with the maturity of human newborns.

Stereotactic body radiation therapy suppresses myeloid-derived suppressor cells by regulating miR-21/Sorbin and SH3 Domain-containing Protein 1 axis.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is a targeted form of radiotherapy used to treat early-stage cancers. Despite its effectiveness, the impact of SBRT on myeloid-derived suppressor cells (MDSCs) is not well understood. In this study, we examined how SBRT affects the differentiation and survival of MDSCs, as well as delved into the molecular mechanisms involved. METHODS AND RESULTS: SBRT was utilized on bone marrow (BM)-derived MDSCs to investigate its impact on the differentiation and survival of MDSCs using flow cytometry. An animal model of lung cancer was created to assess the anti-cancer properties of SBRT and the role of miR-21 expression in MDSCs. The interplay of miR-21 and Sorbin and SH3 domain-containing protein 1 (SORBS1) in MDSC differentiation was explored through dual luciferase activity assay, RT-qPCR, and Western blot analysis. The findings suggest that SBRT led to an increase in miR-21 levels, inhibited MDSC differentiation, and triggered cell apoptosis in BM cells. Inhibition of miR-21 reversed the effects of SBRT on MDSC differentiation and apoptosis. Additionally, it was revealed that SORBS1 was a downstream target of miR-21 in BM cells, and the miR-21/SORBS1 axis played a role in regulating MDSC differentiation and apoptosis induced by SBRT. Modulating miR-21 levels in vivo impinged on the response to SBRT treatment and the quantity of MDSCs in a mouse model of lung cancer. CONCLUSION: Our data indicate that the upregulation of miR-21 induced by SBRT may contribute to the inhibition of MDSC expansion in a lung cancer model.

PI3Kγ inhibition combined with DNA vaccination unleashes a B-cell-dependent antitumor immunity that hampers pancreatic cancer.

Phosphoinositide-3-kinase γ (PI3Kγ) plays a critical role in pancreatic ductal adenocarcinoma (PDA) by driving the recruitment of myeloid-derived suppressor cells (MDSC) into tumor tissues, leading to tumor growth and metastasis. MDSC also impair the efficacy of immunotherapy. In this study we verify the hypothesis that MDSC targeting, via PI3Kγ inhibition, synergizes with α-enolase (ENO1) DNA vaccination in counteracting tumor growth.Mice that received ENO1 vaccination followed by PI3Kγ inhibition had significantly smaller tumors compared to those treated with ENO1 alone or the control group, and correlated with i) increased circulating anti-ENO1 specific IgG and IFNγ secretion by T cells, ii) increased tumor infiltration of CD8+ T cells and M1-like macrophages, as well as up-modulation of T cell activation and M1-like related transcripts, iii) decreased infiltration of Treg FoxP3+ T cells, endothelial cells and pericytes, and down-modulation of the stromal compartment and T cell exhaustion gene transcription, iv) reduction of mature and neo-formed vessels, v) increased follicular helper T cell activation and vi) increased "antigen spreading", as many other tumor-associated antigens were recognized by IgG2c "cytotoxic" antibodies. PDA mouse models genetically devoid of PI3Kγ showed an increased survival and a pattern of transcripts in the tumor area similar to that of pharmacologically-inhibited PI3Kγ-proficient mice. Notably, tumor reduction was abrogated in ENO1 + PI3Kγ inhibition-treated mice in which B cells were depleted.These data highlight a novel role of PI3Kγ in B cell-dependent immunity, suggesting that PI3Kγ depletion strengthens the anti-tumor response elicited by the ENO1 DNA vaccine.

Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer.

Introduction: Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators. Methods: We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival. Results: The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10-5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05-11.56, P = 0.042). Discussion: PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.

Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells.

Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8+ T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.

Dual depletion of myeloid-derived suppressor cells and tumor cells with self-assembled gemcitabine-celecoxib nano-twin drug for cancer chemoimmunotherapy.

Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.