Myeloid-derived Suppressor Cells Research Articles

Multifunctional nanodrug for simultaneously combating chemoresistance and immunosuppression in Fusobacterium nucleatum-associated colorectal cancer.

Fusobacterium nucleatum (Fn) infection in colorectal cancer (CRC) induces chemoresistance and creates an immunosuppressive tumor microenvironment, compromising the efficacy of conventional chemotherapy. To address these challenges, a multifunctional MPLO@HA nanodrug was developed by conjugating metformin (Met), oxaliplatin (OxPt), and lauric acid (LA) onto oligomethyleneimine, subsequently complexed with hyaluronic acid (HA). The MPLO@HA nanodrug is designed to target Fn-infected CRC, offering multiple mechanisms for enhanced therapeutic outcomes. The nanodrug features a multi-stimuli responsive structure that enables precise and controlled release at the tumor site, responsive to pH, glutathione, and hyaluronidase levels. The enhanced positive charge of self-assembled nanodrug combined with Met effectively eradicates both extracellular and intracellular Fn, overcoming Fn-induced chemoresistance. Furthermore, incorporating Met improves the efficacy of chemotherapy by sensitizing CRC cells to treatment. The immunomodulatory properties of the MPLO@HA nanodrug promote immunogenic cell death, repolarize macrophages from the M2 to the M1 phenotype, and reduce the levels of regulatory T cells and myeloid-derived suppressor cells. By integrating antimicrobial, chemotherapeutic, and immunomodulatory capabilities, the MPLO@HA nanodrug offers a promising and comprehensive approach to combating Fn-induced chemoresistance and immunosuppression in CRC. This strategy could also provide a foundation for developing treatments for other cancers associated with bacterial infections. STATEMENT OF SIGNIFICANCE: Fusobacterium nucleatum (Fn) infection in colorectal cancer (CRC) induces chemoresistance and creates an immunosuppressive tumor microenvironment, severely compromising treatment efficacy. Current therapies face challenges in addressing these issues due to the complex interactions between bacterial infection and tumor development. Our study introduces a multifunctional nanodrug, MPLO@HA, which integrates metformin, oxaliplatin, lauric acid, and hyaluronic acid into a multi-responsive nanodrug system. This nanodrug simultaneously combats bacterial infection, chemoresistance, and immunosuppression in Fn-associated CRC. MPLO@HA demonstrates synergistic effects by eradicating both extracellular and intracellular Fn, enhancing chemosensitivity, and modulating the tumor immune microenvironment. This comprehensive approach offers a promising strategy to overcome Fn-induced treatment barriers, potentially improving outcomes for patients with Fn-infected CRC and opening new avenues in bacteria-associated cancer therapy.

Siglec-E augments adipose tissue inflammation by modulating TRAF3 signaling and monocytic myeloid-derived suppressor cells during obesity

BackgroundObesity is associated with dysregulated metabolism and low-grade chronic inflammation in adipose tissue (AT). Immune cells, including macrophages, T cells, and neutrophils, infiltrate the AT and secrete proinflammatory cytokines to exacerbate the AT inflammation. RNA-Seq analysis of AT immune cells isolated from mice fed a high-fat diet (HFD) versus normal fat diet (ND) identified a panel of genes that were markedly downregulated, including sialic acid-binding Ig-like lectin E (siglec-E), in HFD compared to ND mice.MethodsA series of experiments in wild-type (WT) and siglec-E knockout (siglec-E KO) mice was designed to investigate the effect of HFD on the functional role of siglec-E in the regulation of AT inflammation and adipogenesis. We analyzed the changes in immune phenotypes, inflammatory response, adipogenesis, and levels of cytokines and chemokines after HFD and ND feeding.ResultsHFD consumption significantly increased the body weight and blood glucose levels in siglec-E KO mice relative to those of WT mice. This was associated with an increased infiltration of macrophages, CXCR3 expressing CD8 T cells, and monocytic myeloid-derived suppressor cells (M-MDSCs) with a concomitant decrease in numbers of dendritic cells (DCs), in the AT of siglec-E KO fed HFD versus the WT HFD counterparts. The HFD-fed siglec-E KO mice also exhibited elevated expression of intracellular Akt and TNF receptor-associated factor 3 (TRAF3) signaling, inducing C/EBPα, FASN, PPARγ, and resistin in suprascapular AT compared to WT HFD-fed mice. Taken together, these results suggest that a genetic deficiency of siglec-E plays a key role in inducing AT inflammation by differentially altering M-MDSCs and CD8+CXCR3+ T cell function and adipogenesis by TRAF3 and Akt signaling in AT.ConclusionOur findings strongly suggest that modulation of siglec-E pathways might have a protective effect at least in part against AT inflammation and metabolic disorders.

The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer.

Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of Hcar1 in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2+ PMN-MDSCs, enhanced the activation of CD8+ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2+ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2+ PMN-MDSCs, boosted CD8+ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2+ PMN-MDSCs as a mechanism of immunosuppression.

Exploring the Immunological Aspects and Treatments of Recurrent Pregnancy Loss and Recurrent Implantation Failure

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation. It affects 3–5% of women who are attempting to conceive. RPL can stem from a variety of causes and is frequently associated with psychological distress and a diminished quality of life. By contrast, recurrent implantation failure (RIF) refers to the inability to achieve a successful pregnancy after three or more high-quality embryo transfers or at least two instances of egg donation. RIF shares several causative factors with RPL. The immunological underpinnings of these conditions involve alterations in uterine NK cells, reductions in M2 macrophages and myeloid-derived suppressor cells, an increased Th1/Th2 ratio, a decreased Treg/Th17 ratio, the presence of shared ≥3 HLA alleles between partners, and autoimmune disorders. Various therapeutic approaches have been employed to address these immunological concerns, achieving varying degrees of success, although some therapies remain contentious within the medical community. This review intends to explore the immunological factors implicated in RPL and RIF and to analyze the immunological treatments employed for these conditions, which may include steroids, intravenous immunoglobulins, calcineurin inhibitors, anti-TNF antibodies, intralipid infusions, granulocyte colony-stimulating factor, and lymphocyte immunotherapy.

HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact on MDSCs remains elusive. We sought to investigate the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. Our results indicate that HDAC1-3 inhibitors reduce CCR2 expression, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotropic hepatocellular carcinoma (HCC) murine model, HDAC1-3 inhibitors reduced the infiltration of M-MDSCs, increased the number of natural killer cells in tumors, and suppressed tumor growth. Our results also suggest that HDAC1-3 inhibitors potentiate the antitumor effects of anti-programmed cell death protein 1 antibodies. ATAC-seq and RNA-seq analyses revealed 115 genes epigenetically upregulated by HDAC1-3 inhibitors, primarily linked to transcriptional regulation and ubiquitination. We further elucidated that HDAC1-3 inhibitors facilitate CCR2 protein degradation through ubiquitination-mediated by NEDD4 E3 ligase. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential synergistic immunotherapy strategy for clinical benefit in HCC.

Phase II single-arm, single-center clinical trial of all-trans-retinoic acid, bevacizumab, and atezolizumab in refractory microsatellite stable colorectal cancer.

TPS324 Background: A critical clinical challenge in microsatellite stable (MSS) metastatic colorectal (mCRC) patients is to identify strategies to overcome lack of response to immune checkpoint inhibitors. An immunosuppressive tumor microenvironment comprising myeloid-derived suppressor cells (MDSC), endothelial cells, regulatory T cells, tumor associated macrophages, and cancer associated fibroblasts promotes immune evasion and resistance to these agents. MDSCs are bone marrow derived myeloid cells that suppress T-cell function and promote tumor growth. Among all cancers, mCRC patients have one of the highest frequency of MDSC (CD11b+, CD33+, CD14+ HLA-DRneg) in blood (1). It was demonstrated that altering the MDSC% in the tumor microenvironment by ATRA and anti-VEGF therapy (bevacizumab) can enhance the effects of immune checkpoint inhibitors (2-4). The hypothesis of the current clinical trial is that the combination of ATRA, bevacizumab and atezolizumab will lead to a decrease in MDSC population in tumor microenvironment leading to a clinically meaningful improvement in response rates among refractory MSS mCRC patients. Methods: This is a single-arm, open-label, phase 2 clinical trial combining ATRA, bevacizumab, and atezolizumab in refractory MSS mCRC patients. It will enroll a total of 21 patients over 24 months at UT Southwestern Medical Center that are MSS by PCR or NGS testing or are proficient in immunohistochemical expression of all four mismatch repair enzymes (MLH1, MSH2, MSH6, PMS2). ATRA will be administered orally at 45 mg/m2/day in 2 divided doses on days 1-7 and repeated every 14 days; atezolizumab will be given intravenously on day 1 at 840 mg dose every 14 days, and bevacizumab will be administered intravenously on day 1 at 10 mg/kg dose every 14 days. The first six patients enrolled on this study will contribute to the safety lead-in phase of this study. The primary outcome is to assess the overall response rate by RECIST v1.1. Secondary outcomes include assessment of disease control rate and frequency of adverse events using CTCAE v5.0. Exploratory outcomes include assessment of PFS and OS and collecting blood and tissue samples at defined timelines to study the changes in the MDSC population among responders and non-responders (NCT05999812). 1. Kobayashi, M. et. al., Clin Cancer Res, 2019. 2. Mirza, N., et al., Cancer Res, 2006. 3. Tobin, R.P., et al., Int Immunopharmacol, 2018. 4. Tobin, R.P., et. al., Clin Can Res, 2023. Clinical trial information: NCT05999812 .

VEGF-A as a prognostic indicator in advanced gastric and colorectal cancers and correlation with immune suppression involving myeloid-derived suppressor cells (MDSC).

250 Background: VEGF-A is important molecule should be controlled in cancer treatment since hypoxic and immunosuppressive conditions of tumor microenvironment are induced by VEGF-A. Myeloid-derived suppressor cells (MDSC), activated by chronic inflammation and VEGF-A, play critical roles in immunosuppression in patients with cancer. Methods: Serum levels of VEGF-A were measured by ELISA and circulating levels of MDSC were measured by Flow Cytometry (CD11b+, CD14-, CD33+). Patients with gastric and colorectal cancers were divided into two groups, high VEGF group (serum VEGF-A>330pg/ml) and lo group (≤330pg/ml). Results: Prognosis of stages III and IV gastric cancer with high VEGF-A was significantly worse than in low VEGF-A group, while difference was not significant in stages I and II. In colorectal cancer, the results were exactly same as found in gastric cancer. The levels of MDSC were significantly correlated with the levels of VEGF-A in patients with gastric and colorectal cancers. The levels of VEGF-A were also correlated with inflammatory markers including CRP and NLR (neutrophil to lymphocyte ratio), and inversely did to stimulation index of lymphocyte proliferation (SI: parameter of cellular immune reaction) and nutritional parameters such as albumin or rapid turnover protein. Conclusions: The observation in the present study suggest that VEGF-A is closely associated with inflammation-associated disease progression especially in advanced stages, and serve as useful marker of immunosuppression involving MDSC and prognosis in patients with gastric and colorectal cancers.

Expanded biomarker analysis of an international, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).

635 Background: The optimal treatment for patients (pts) with advanced HCC who progress on an ICI-containing regimen has not been defined. In pts who progressed on one prior ICI regimen, regorafenib plus pembrolizumab (rego + pembro) showed modest anti-tumor activity (primary completion analysis: overall objective response rate 7.4%, all partial responses [PR]) and an expected safety profile (NCT04696055; El-Khoueiry, ASCO 2024). We conducted additional exploratory analyses of tumor markers to gain insights into the clinical results. Methods: Overall, 95 adults with unresectable advanced HCC (C-P Class A, BCLC stage B/C, ECOG PS 0/1) received oral regorafenib 90 mg once daily 3 weeks on/1 week off plus pembrolizumab 400 mg i.v. every 6 weeks. Prior treatment: Cohort 1 = atezolizumab + bevacizumab (n=68); Cohort 2 = any other ICI alone or in combination (n=27). Biomarker analyses in subsets of pts explored potential correlations with clinical benefit (defined as tumor response or stable disease [SD] ≥ 4 months). Immune cell subtypes in blood were analyzed by flow cytometry. Tumor immune markers were assessed by immunohistochemistry. Gene expression profiling in tumor samples was by RNAseq. Results: Twenty-one pts had baseline samples for RNAseq, 7 of whom had clinical benefit (n= 3 Cohort 1 [including 1 PR], n=4 Cohort 2). Pts with clinical benefit had differential gene expression at baseline including enriched expression of genes associated with Notch, Hedgehog, fibroblast, TGF-β, and insulin-like growth factor binding protein signaling; in contrast, there was higher expression of genes associated with myeloid derived suppressor cells in pts without clinical benefit. Of note, tumor samples from pts in this study had increased Tregs and T-cell exhaustion signatures compared with pts treated with rego + pembro in a first-line study (NCT03347292).Analyses of available paired tumor samples from 4 patients (n=2 SD, n=2 progressive disease) found reductions in activated fibroblast, TGF-β, and collagen gene expression signatures from baseline to Week 6 Day 1 of treatment. Conclusions: Rego + pembro had modest activity in pts who progressed on one prior ICI-based regimen. Exploratory biomarker analyses suggest different gene expression in pts with or without clinical benefit. Clinical benefit was associated with enriched expression of genes in Notch, Hedgehog, fibroblast, and TGF-β pathways. Pre- and post-treatment biopsies showed reductions in fibroblast, TGF-β, and collagen gene expression, which are known features of HCC. In the context of the limitations of small sample size and absence of a control arm, these findings are hypothesis generating and consistent with HCC biology and regorafenib mechanism of action. Clinical trial information: NCT04696055 .

Overcoming Immunotherapy Resistance in Hepatocellular Carcinoma by Targeting Myeloid IL-8/ CXCR2 Signaling.

Durable response to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) are limited to a minority of patients, yet reliable biomarkers are still lacking. Inflammatory cytokines such as interleukin-8 (IL-8) are associated with HCC progression, and IL-8 is known as the chemoattractant for immunosuppressive myeloid cells. Therefore, we aim to elucidate the ICB resistance mechanisms mediated by the activation of the IL-8/CXCR2 pathway. Single-cell RNA sequencing (scRNA-seq) were performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a Phase II clinical trial cohort. Our data revealed that IL-8 and its receptor, CXCR2 mainly derived from the immunosuppressive myeloid derived suppressor cells (MDSCs). Particularly, high circulating IL-8 level strongly associated with poor ICB response. This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist. Suppression of IL-8/CXCR2 pathway significantly abrogated MDSCs trafficking and immunosuppressive activity, which sensitized the anti-PD-L1 blockade to reduce tumor growth and prolong survival. The association between myeloid IL-8 and ICB therapeutic outcome also extended to multiple cancer types. Collectively, our study not only suggests a potential non-invasive biomarker for patient stratification and monitoring of ICB response, but also provides a proof-of-concept for combinational immunotherapy to benefit patients who are non-responsive to ICB monotherapy.

Safety and biomarker assessment of ST316, a novel peptide antagonist of ß-catenin, in patients with advanced solid tumors.

286 Background: Constitutive activation of ß-catenin, resulting in its nuclear accumulation and deregulated transcriptional activity, is a key event in colorectal cancer (CRC). Additionally, pathway mutations correlate with immune exclusion in CRC and across different tumor types. Disruption of the interaction of ß-catenin and its co-activator BCL9 is sufficient to suppress oncogenic ß-catenin transcriptional activity, without impacting its homeostatic functions in normal tissue. ST316 is a first-in-class, cell-penetrating peptide antagonist of the ß-catenin and BCL9 interaction. Preclinical evaluation revealed significant bioavailability and potent activity in CRC models with no impact on ß-catenin homeostatic functions such as intestinal stem cell survival or bone morphology. Methods: A phase 1-2 (P1-2) escalation-expansion study has enrolled patients (pts) with advanced solid tumors likely to harbor abnormalities in the Wnt/ß-catenin pathway, to assess the safety, pharmacokinetics (PK), biomarker and preliminary activity of ST316, and to recommend a P2 dose (RP2D). Paired biopsies were collected when feasible and assessed for drug penetration and pharmacodynamic biomarkers. Peripheral blood (PB) collected pre- and post-treatment was assessed by flow cytometry for polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Results: As of Sep.24, 2024; 23 pts with CRC (N=14), NSCLC (N=4), PDAC (N=2), or Breast and Ovarian cancer (N=1, each), were treated in 6 cohorts (0.5-12mg/kg) with IV ST316, once weekly. Treatment related AEs were observed in 17/23 pts and were mostly low grade, except for 2 G3 AEs that resolved: Fatigue (1) and ALT/AST elevation (1). No dose-limiting toxicities (DLTs) were observed. Single agent ST316 showed disease stabilization in 4 pts. PK analysis showed dose-proportional increases in Cmax and AUC for doses up to 8 mg/kg. IHC analysis showed substantial tumor penetration of ST316 in all analyzed samples and evidence of a treatment-induced redistribution of β-catenin in a subset of pts. PB analysis indicated high baseline levels of the ß-catenin-driven immunosuppressive PMN-MDSCs , followed by a significant decrease after ST316 exposure (p<0.005). The RP2D selected for combination cohorts in CRC is 8mg/kg; additional PD assessments are ongoing. Conclusions: Monotherapy ST316 was well-tolerated with dose-proportional PK and substantial tumor uptake. Pharmacodynamic analyses demonstrate mechanistic evidence of antagonism of ß-catenin signaling, including redistribution of ß-catenin subcellular localization and significant depletion of the ß-catenin-driven immunosuppressive PMN-MDSC population. Based on these data, ST316 advanced into P2 in CRC pts in combination with SoC in 2 nd and 3 rd line. Clinical trial information: NCT05848739 .

Monocyte-macrophage dynamics as key in disparate lung and peripheral immune responses in severe anti-melanoma differentiation-associated gene 5-positive dermatomyositis-related interstitial lung disease.

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+ DM) is a rare inflammatory autoimmune disorder often complicated by life-threatening rapidly progressive interstitial lung disease (RP-ILD). The underlying mechanisms driving immune dysfunction and lung injury, however, remain poorly understood. The study aims to gain insights into the disrupted immune landscape in peripheral and pulmonary compartments of severe anti-MDA5+ DM and explore potential therapeutic targets. We employed single-cell RNA sequencing to examine cellular constituents within five patients' bronchoalveolar lavage fluid and paired peripheral blood mononuclear cells. Luminex assay and flow cytometry were further applied to validate the results. Our analysis revealed starkly contrasting immune landscapes between the periphery and lungs, with peripheral immune suppression juxtaposed against pulmonary immune hyperactivation. Central to this dysregulation was the monocyte-macrophage lineage. Circulating monocytes exhibited an immunosuppressive phenotype, characterised by diminished cytokine production, reduced MHC II expression, and features resembling myeloid-derived suppressor cells. These monocytes were recruited to the lungs, where they differentiated into monocyte-derived alveolar macrophages (Mo-AMs) with robust proinflammatory and profibrotic activities. Mo-AMs drove cytokine storms and produced chemokines that amplified inflammatory cell recruitment and lung tissue remodelling. Additionally, peripheral T and NK cells exhibited increased cell death and active migration into the lungs, which may be the cause of lymphopenia. Our study underscores the pivotal role of monocyte-macrophage dynamics in the immunopathogenesis of anti-MDA5+-associated RP-ILD, offering critical insights into compartment-specific immune dysregulation. These findings suggest potential therapeutic strategies targeting monocyte recruitment and macrophage activation to mitigate disease progression. Peripheral immune suppression and pulmonary immune hyperactivation characterise the distinct immune landscapes in anti-MDA5+DM with RP-ILD. Circulating monocytes transition from an immunosuppressive phenotype in the periphery to proinflammatory and profibrotic Mo-AMs in the lungs. Chemokines produced by Mo-AMs drive monocyte and other immune cell recruitment to the lungs, amplifying pulmonary inflammation.

Neoadjuvant clinical trials in adults with newly diagnosed high-grade glioma: A systematic review.

High-grade gliomas are devastating cancers that remain incurable with standard surgical resection and radiochemotherapy. Although beneficial against neoplasms, radiation lowers lymphocyte counts, weakens immune activation, and recruits suppressive myeloid cells impairing immune responses. Tumor environments treated with radiation experience long-term immunosuppression, reducing immunotherapy effectiveness and contributing to recurrence. Investigating pre-radiation treatments in newly diagnosed patients could identify active agents, assess immunotherapy impact, and enable multiomic analyses without radiation-induced confounding factors. This literature review was conducted to describe the feasibility, safety, and outcomes of postsurgical, pre-radiation clinical trials for adults with newly diagnosed high-grade glioma. A systematic review was performed of the English-language literature reporting results of clinical trials for adults with newly diagnosed high-grade glioma administered postsurgical treatment prior to radiation therapy. A search was conducted in PubMed and references cited in research and review articles were also considered. From 1991 to 2024, 52 clinical trials were identified: 3 phase I, 38 phase II, 4 phase III, and 7 of unknown phase. Nine trials were randomized, 24 were multicenter trials, 21 investigated temozolomide-containing regimens, and 12 focused on inoperable tumors, involving a total of 2737 patients. Pre-radiation neoadjuvant studies are feasible and may identify active drugs. This is particularly relevant in the era of personalized medicine with brain-penetrant drugs, targeted therapy, and immuno-oncology advancements. Investigating pre-radiation treatments in newly diagnosed high-grade glioma is a viable approach to rapidly identify active and inactive regimens while the immune system and tumor microenvironment remain intact.

Platinum(IV) Complexes Trigger Death Receptors and Natural Killer Cells to Suppress Breast Cancer.

Chemoimmunotherapy is an alternative treatment against cancers. Platinum(IV) complexes FMP and DFMP, coupling formononetin derivative as axial ligand(s), were designed to suppress triple-negative breast cancer (TNBC) by activating death receptors (DRs) and natural killer (NK) cells. These complexes show great potential to overcome the resistance of TNBC to chemotherapy by inducing both intrinsic and extrinsic apoptosis in cancer cells. Particularly, FMP with one axial formononetin derivative not only induced the caspase-3-dependent intrinsic apoptosis but also upregulated the expression of DRs and caspase-8, triggered the extrinsic apoptosis, and enhanced the cytotoxic ability of NK92 cells. Moreover, FMP increased the release of granzyme B, restrained the proliferation and differentiation of myeloid-derived suppressor cells, and the secretion of IL-10, thus inhibiting the TNBC in vitro and in vivo. The results demonstrate that FMP overcomes the chemoresistance and immune escape of TNBC through a new mechanism involving the synergy of chemotherapy and immunotherapy.

Peripheral blood leukocyte signatures as biomarkers in relapsed ovarian cancer patients receiving combined anti-CD73/anti-PD-L1 immunotherapy in arm A of the NSGO-OV-UMB1/ENGOT-OV30 trial.

Immune checkpoint inhibitors have demonstrated limited efficacy in overcoming immunosuppression in patients with epithelial ovarian cancer (EOC). Although certain patients experience long-term treatment benefit, reliable biomarkers for responder pre-selection and the distinction of dominant immunosuppressive mechanisms have yet to be identified. Here, we used a 40-marker suspension mass cytometry panel to comprehensively phenotype peripheral blood leukocytes sampled over time from patients with relapsed EOC who underwent combination oleclumab (anti-CD73) and durvalumab (anti-PD-L1) immunotherapy in the NSGO-OV-UMB1/ENGOT-OV30 trial. We found that survival duration was impacted by baseline abundances of total peripheral blood mononuclear cells. Longitudinal analyses revealed a significant increase in CD14+CD16- myeloid cells during treatment, with significant expansion of monocytic myeloid-derived suppressor cells occurring in patients with shorter progression-free survival, who additionally showed a continuous decrease in central memory T-cell abundances. All patients demonstrated significant PD-L1 upregulation over time on most T-cell subsets. Higher CD73 and IDO1 expression on certain leukocytes at baseline significantly positively correlated with longer progression-free survival. Overall, our study proposes potential biomarkers for EOC immunotherapy personalization and response monitoring; however, further validation in larger studies is needed.

Myeloid-derived suppressor cells exhibit distinct characteristics in bone marrow and blood of individuals with diffuse large B-cell lymphoma

Antitumor immune surveillance is the key feature of tumour progression and response to treatment in various malignancies, such as lymphomas. Myeloid derived suppressor cells (MDSCs) are bone marrow (BM)-derived cells with potent suppressive properties, implicated in T cell inhibition and tumour dissemination. In Diffuse Large B-cell Lymphoma (DLBCL), circulating MDSCs constitute the immunosuppressive tumor microenvironment, while the contribution of BM MDSCs in disease pathogenesis remains elusive. In the present study we aimed to evaluate both the frequencies as well as the molecular signatures of MDSCs in blood and BM from newly diagnosed DLBCL patients prior to treatment initiation and from age matched healthy donors. Circulating levels of total, monocytic (M-) and polymorphonuclear (PMN-) MDSCs were found increased in DLBCL compared to healthy control, while in DLBCL patients the BM MDSCs were significantly increased compared to blood. Transcriptomic analysis revealed significantly different molecular fingerprints to characterize circulating and BM M-MDSCs, implying that MDSCs exhibit their function with distinct mechanisms depending on the anatomical compartment. Despite that MDSC frequencies did not demonstrate any significant correlation with disease characteristics and outcome, our findings propose that gene expression profiling should be evaluated for their potential prognostic impact. Overall, the findings presented here, provide new insights in the immunosuppressive networks that operate in DLBCL and importantly propose new molecular mechanisms expressed by BM MDSCs which may be explored therapeutically.

A comparison of myeloid-derived suppressor cell populations in patients with ulcerated vs non-ulcerated melanoma receiving immune checkpoint blockade.

Myeloid-derived suppressor cells (MDSCs) are expanded in cancer patients, have an intrinsic immunosuppressive function, and thus may play a role in resistance to immunotherapy. Ulceration of the melanoma primary is associated with more aggressive disease and is an independent prognostic factor for melanoma-specific survival. However, the underlying factors contributing to this more aggressive phenotype are not completely understood. The current study aims to correlate changes in circulating MDSC during immunotherapy in patients with ulcerated vs non-ulcerated melanoma primary tumors. Longitudinal changes in levels of circulating MDSCs were analyzed via flow cytometry in melanoma patients receiving immune checkpoint inhibitors (ICIs) and stratified by ulceration status. Following the initiation of therapy, the percentage of total MDSCs increased significantly in patients with both ulcerated (P = 0.003) and non-ulcerated (P < 0.001) tumors. When MDSCs were stratified by subset, the proportion of granulocytic MDSC (PMN-MDSC) decreased in patients with non-ulcerated tumors (P = 0.023), while the proportion remained stable in patients with ulcerated tumors (P = 0.121). The reduction in the proportion PMN-MDSC in non-ulcerated patients coincided with a statistically significant increase in the proportion of CD14+/CD15+ MDSC (P = 0.008), resulting in a greater proportion of CD14+/CD15+ MDSC in non-ulcerated patients as compared to ulcerated melanoma patients following two infusions of ICIs (27.3 ± 19.2% vs 16.1 ± 19.2%; P = 0.008). The trajectories of the MDSC populations described here provide insight into the altered tumor microenvironment in ulcerated melanoma and highlight key changes in a cell population that could contribute to immunotherapy resistance.

P-1866. Polymorphonuclear Myeloid-Derived Suppressor Cells regulates immune reconstitution during HIV infection through PD-L1 and TGF-β signaling

Abstract Background Although myeloid-derived suppressor cells (MDSCs) are widely recognized for their immunoinhibitory effect in a variety of pathological conditions, their function during human immunodeficiency virus (HIV) infection and the onset of inadequate immune reconstitution remains elusive. PMN-MDSCs inhibit autologous CD4+ T-cell proliferation and cytokines (IL-2, TNF-α, and IFN-γ) production in HIV INRs. Methods We conducted a cross-sectional study in which 30 healthy controls (HC) and 62 HIV-1-infected subjects [31 immunological non-responders (INRs) and 31 immunological responders (IRs)] were selected. After two years of antiretroviral therapy, INRs and IRs were designated as patients with CD4+ T-cell counts &amp;lt; 350 cells/μL and &amp;gt;500 cells/μL, respectively. The proportion of MDSCs was measured and their relationship with HIV disease progression was studied. Specifically, using flow cytometry and real-time PCR, immune regulatory molecules (including programmed death-ligand 1 [PD-L1], arginase 1, inducible nitric oxide synthase, interleukin 10, transforming growth factor beta [TGF-β], and indoleamine 2,3-dioxygenase) that are relevant for MDSCs activity were quantified. Furthermore, we investigated the impact of the blockade of PD-L1 and/or TGF-β signaling on MDSCs and their effects on CD4+ T cells using in vitro functional experiments. PD-L1 and TGF-β mediate the suppressive effect of PMN-MDSCs on CD4+ T-cells response. Results We found that polymorphonuclear MDSCs (PMN-MDSCs) are more abundant and negatively correlated with CD4+ T-cell counts in HIV-infected individuals. PMN-MDSCs suppress CD4+ T-cell proliferation and interferon-γ (IFN-γ) production in INRs. Furthermore, correlations were found between PD-L1 expression on PMN-MDSCs and PD-1+ CD4+ T-cells. TGF-β expression on PMN-MDSCs was likewise enhanced in INRs. Importantly, inhibiting both PD-L1 and TGF-β signaling had a synergistic impact on restoring CD4+ T-cell activity in vitro. Conclusion Our findings reveal that the expansion of PMN-MDSCs decreased CD4+ T-cell proliferation and IFN-γ secretion in HIV infection through PD-L1 and TGF-β mediated pathways. Interventions that target both PD-L1 and TGF-β pathways may be novel strategies for enhancing immune reconstitution in INRs. Disclosures All Authors: No reported disclosures

Sorafenib enhanced the function of myeloid-derived suppressor cells in hepatocellular carcinoma by facilitating PPARα-mediated fatty acid oxidation

BackgroundSorafenib, an FDA-approved drug for advanced hepatocellular carcinoma (HCC), faces resistance issues, partly due to myeloid-derived suppressor cells (MDSCs) that enhance immunosuppression in the tumor microenvironment (TME).MethodsVarious murine HCC cell lines and MDSCs were used in a series of in vitro and in vivo experiments. These included subcutaneous tumor models, cell viability assays, flow cytometry, immunohistochemistry, and RNA sequencing. MDSCs were analyzed for chemotaxis, immunosuppressive functions, fatty acid oxidation (FAO), and PPARα expression. The impact of sorafenib on tumor growth, MDSC infiltration, differentiation, and immunosuppressive function was assessed, alongside the modulation of these processes by PPARα.ResultsHere, we revealed increased infiltration and enhanced function of MDSCs in TME after treatment with sorafenib. Moreover, our results indicated that sorafenib induced the accumulation of MDSCs mediated by CCR2, and pharmacological blockade of CCR2 markedly reduced MDSCs migration and tumor growth. Mechanistically, sorafenib promoted the effect and fatty acid uptake ability of MDSCs and modulated peroxisome proliferator-activated receptor α (PPARα)-mediated fatty acid oxidation (FAO). In addition, tumor-bearing mice fed a high-fat diet (HFD) at the beginning of sorafenib administration had worse outcomes than mice fed a regular diet. Genetic deficiency of PPARα weakens the effect of sorafenib on MDSCs in mice with HCC. Pharmacological inhibition of PPARα has a synergistic anti-tumor effect with sorafenib, which is attenuated by the inhibition of MDSCs. Mechanistically, sorafenib significantly inhibited the differentiation of macrophages by upregulating PPARα expression and suppressing the PU.1-CSF1R pathway.ConclusionOverall, our study demonstrated that sorafenib enhanced the function of MDSCs by facilitating PPARα-mediated FAO and further augmenting sorafenib resistance, which sheds light on dietary management and improves the therapeutic response in HCC.

Regulatory Immune Cell-derived Exosomes: Modes of Action and Therapeutic Potential in Transplantation.

Reduced dependence on antirejection agents, improved long-term allograft survival, and induction of operational tolerance remain major unmet needs in organ transplantation due to the limitations of current immunosuppressive therapies. To address this challenge, investigators are exploring the therapeutic potential of adoptively transferred host- or donor-derived regulatory immune cells. Extracellular vesicles of endosomal origin (exosomes) secreted by these cells seem to be important contributors to their immunoregulatory properties. Twenty years ago, it was first reported that donor-derived exosomes could extend the survival of transplanted organs in rodents. Recent studies have revealed that regulatory immune cells, such as regulatory myeloid cells (dendritic cells, macrophages, or myeloid-derived suppressor cells), regulatory T cells, or mesenchymal stem/stromal cells can suppress graft rejection via exosomes that express a cargo of immunosuppressive molecules. These include cell surface molecules that interact with adaptive immune cell receptors, immunoregulatory enzymes, and micro- and long noncoding RNAs that can regulate inflammatory gene expression via posttranscriptional changes and promote tolerance through promotion of regulatory T cells. This overview analyzes the diverse molecules and mechanisms that enable regulatory immune cell-derived exosomes to modulate alloimmunity and promote experimental transplant tolerance. We also discuss the potential benefits and limitations of their application as therapeutic entities in organ transplantation.

Role of Crosstalk Between Gut Microbiota and Immune Cells in Colorectal Cancer: A Narrative Review

Abstract Colorectal cancer (CRC) ranks among the most prevalent and deadly cancers globally, with its incidence increasing due to lifestyle factors such as increased consumption of red meat and decreased vegetable intake. A distinctive aspect of CRC is its strong connection to the gut microbiota, which is crucial in both tumorigenesis and immune regulation. This narrative review provides a comprehensive analysis of the interactions between gut microbiota and the immune system, focusing on their importance in CRC progression and responses to immunotherapy. Imbalances in the composition of gut microbes are strongly associated with CRC development. Notably, species such as Fusobacterium nucleatum and Bacteroides fragilis have been identified as key regulators of immune responses within the tumor microenvironment. These microbes affect the functions of immune cells, such as T cells, macrophages and myeloid-derived suppressor cells, thereby influencing cancer progression and prognosis. Additionally, this review underscores the potential of gut microbiota as biomarkers for CRC detection and outcome prediction. There is also growing interest in the use of probiotics, fecal microbiota transplantation and dietary modifications as supplementary treatments. A deeper understanding of how microbial communities interact with the immune system may pave the way for novel personalized therapies, particularly by enhancing the effectiveness of immune checkpoint inhibitors.