Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoMϕ). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.

Myeloid-Derived Suppressor Cells (MDSCs) in Haematology

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunomodulating properties, mainly acting by suppressing T-cell responses [...]

Myeloid-Derived Suppressor Cells: A Multifaceted Accomplice in Tumor Progression

Myeloid-derived suppressor cell (MDSC) is a heterogeneous population of immature myeloid cells, has a pivotal role in negatively regulating immune response, promoting tumor progression, creating pre-metastases niche, and weakening immunotherapy efficacy. The underlying mechanisms are complex and diverse, including immunosuppressive functions (such as inhibition of cytotoxic T cells and recruitment of regulatory T cells) and non-immunological functions (mediating stemness and promoting angiogenesis). Moreover, MDSC may predict therapeutic response as a poor prognosis biomarker among multiple tumors. Accumulating evidence indicates targeting MDSC can reverse immunosuppressive tumor microenvironment, and improve therapeutic response either single or combination with immunotherapy. This review summarizes the phenotype and definite mechanisms of MDSCs in tumor progression, and provide new insights of targeting strategies regarding to their clinical applications.

Biophysical and pharmacokinetic characterization of a small-molecule inhibitor of RUNX1/ETO tetramerization with anti-leukemic effects

Acute myeloid leukemia (AML) is a malignant disease of immature myeloid cells and the most prevalent acute leukemia among adults. The oncogenic homo-tetrameric fusion protein RUNX1/ETO results from the chromosomal translocation t(8;21) and is found in AML patients. The nervy homology region 2 (NHR2) domain of ETO mediates tetramerization; this oligomerization is essential for oncogenic activity. Previously, we identified the first-in-class small-molecule inhibitor of NHR2 tetramer formation, 7.44, which was shown to specifically interfere with NHR2, restore gene expression down-regulated by RUNX1/ETO, inhibit the proliferation of RUNX1/ETO-depending SKNO-1 cells, and reduce the RUNX1/ETO-related tumor growth in a mouse model. However, no biophysical and structural characterization of 7.44 binding to the NHR2 domain has been reported. Likewise, the compound has not been characterized as to physicochemical, pharmacokinetic, and toxicological properties. Here, we characterize the interaction between the NHR2 domain of RUNX1/ETO and 7.44 by biophysical assays and show that 7.44 interferes with NHR2 tetramer stability and leads to an increase in the dimer population of NHR2. The affinity of 7.44 with respect to binding to NHR2 is Klig = 3.95 +/- 1.28 micromolar. By NMR spectroscopy combined with molecular dynamics simulations, we show that 7.44 binds with both heteroaromatic moieties to NHR2 and interacts with or leads to conformational changes in the N-termini of the NHR2 tetramer. Finally, we demonstrate that 7.44 has favorable physicochemical, pharmacokinetic, and toxicological properties. Together with biochemical, cellular, and in vivo assessments, the results reveal 7.44 as a lead for further optimization towards targeted therapy of t(8;21) AML.

Targeting Myeloid-Derived Suppressor Cells to Enhance the Antitumor Efficacy of Immune Checkpoint Blockade Therapy

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are activated under pathological conditions, such as cancer, or mature myeloid cells that are converted immune-suppressive cells via tumor-derived exosomes, and potently support the tumor processes at different levels. Currently, multiple studies have demonstrated that MDSCs induce immune checkpoint blockade (ICB) therapy resistance through their contribution to the immunosuppressive network in the tumor microenvironment. In addition, non-immunosuppressive mechanisms of MDSCs such as promotion of angiogenesis and induction of cancer stem cells also exert a powerful role in tumor progression. Thus, MDSCs are potential therapeutic targets to enhance the antitumor efficacy of ICB therapy in cases of multiple cancers. This review focuses on the tumor-promoting mechanism of MDSCs and provides an overview of current strategies that target MDSCs with the objective of enhancing the antitumor efficacy of ICB therapy.

Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells derived from immature myeloid cells. These cells are often associated with poor responses to cancer therapy, including immunotherapy, in a variety of tumor types. The C-X-C chemokine receptor 2 (CXCR2) signaling axis plays a key role in the migration of immunosuppressive MDSCs into the tumor microenvironment (TME) and the pre-metastatic niche. MDSCs impede the efficacy of immunotherapy through a variety of mechanisms. Efforts to target MDSCs by blocking CXCR2 is an active area of research as a method for improving existing and novel immunotherapy strategies. As immunotherapies gain approval for a wider array of clinical indications, it will become even more important to understand the efficacy of CXCR2 inhibition in combating immunotherapy resistance at different stages of tumor progression.

TERT genetic variability and telomere length as factors affecting survival and risk in acute myeloid leukaemia

Acute myeloid leukaemia (AML) is a neoplasm of immature myeloid cells characterized by various cytogenetic alterations. The present study showed that in addition to the FLT3-ITD and NPM1 mutation status, telomere length (TL) and telomerase reverse transcriptase (TERT) gene polymorphisms may affect risk and overall survival (OS) in AML. TL was longer in healthy controls than in AML patients and positively correlated with age in the patients, but not in healthy subjects. TL was found to be independently affected by the presence of the FLT3-ITD mutation. As for the TERT gene polymorphism, AML patients with the TERT rs2853669 CC genotype were characterized by significantly shorter OS than patients carrying the T allele. Another observation in our study is the difference in TL and OS in patients belonging to various risk stratification groups related to the FLT3-ITD and NPM1 mutation status. Patients with adverse risk classification (mutation in FLT3-ITD and lack of mutation in NPM1) presented with the shortest telomeres and significantly worse OS. In conclusion, OS of AML patients appears to be affected by TERT gene variability and TL in addition to other well-established factors such as age, WBC count, or FLT3-ITD and NPM1 mutation status.

Rare Case of Mediastinal Myeloid Sarcoma

Myeloid sarcoma is a rare tumor mass with extra medullary growth pattern, composed of myeloblast or immature myeloid cells. Myeloid sarcoma (MS) is a distinct clinical presentation of acute myeloid leukemia (AML) where less than 1% of patients present with prominent extra medullary disease which most commonly involves the bone, skin, lymph node, soft tissues, gastrointestinal tract or testes. The recommended treatment regimen in isolated myeloid sarcoma or with bone marrow involvement is upfront systemic chemotherapy. We report a case of a young female with anterior mediastinal mass diagnosed as myeloid sarcoma which was refractory to chemotherapy.

Peripheral Levels of Monocytic Myeloid-Derived Suppressive Cells at Diagnosis Predict Survivals in AML Patients Eligible for Intensive Chemotherapy

Introduction: Myeloid Derived Suppressive Cells (MDSC) constitute a heterogeneous population of immature myeloid cells characterized by their capacity to suppress innate and adaptive immune responses. As such, they have been proven, in solid tumors, to modulate malignancy by increasing tumor cell survival, angiogenesis, metastasis and tissue invasion. By contrast, reports on the role of MDSC in either acute myeloid (AML) or lymphoid (ALL) leukemias are very limited with unknown established impact on long-term outcomes. Patients and Methods: This monocentric prospective study included all adult patients eligible for first-line intensive chemotherapy for AML or ALL. The main objective was to investigate the presence of peripheral blood monocytic MDSC at diagnosis and after induction in such patients and to correlate their levels to complete remission (CR/CR with incomplete platelet recovery), cytologic relapse, leukemia-free (LFS) and overall (OS) survivals. Monocytic MDSCs were defined as CD15- CD34- CD16- CD14+ CD33+ CD11b+ DR-/low cells and assessed in a lysis-no-wash flow cytometry technique. Data acquisition was performed on a Navios® flow cytometer (Beckman Coulter, Miami, FL). MDSC were expressed as a percentage (%) of total nucleated cells defined as CD45+. MDSC% were compared to those of 21 healthy controls. The study was registered at the French Commission Nationale de l'Informatique et des Libertés as CNIL 2016-038. All patients gave informed consent. Analyses were performed in July 2021. Results: Between October 2017 and March 2021, 73 AML and 14 ALL were enrolled (Table 1). The median MDSC% in controls was 0.24% (range: 0.02-1.21). This % was significantly higher in AML compared to ALL (0.19% (range: 0-0.54) vs 0.14% (range: 0-0.35), p=0,01) and differed significantly from controls in ALL (p=0.0004) but not in AML (p=0.94). MDSC% after chemotherapy induction were available for 61 AML and 13 ALL at medians of 37,5 and 37 days, respectively. At that time, median MDSC% were similar between AML (0.84%, range: 0-28) and ALL (0.97%, range: 0-4.75) patients (p=0.52) but significantly higher than in controls for AML patients (p=0.001; ALL p=0.07). AML: MDSC% were not correlated to any other factors, especially ELN2017 classification (p=0.79). ROC curves for LFS established the threshold of 0,55% of MDSC at diagnosis as the best cut-off for analyses. MDSC% (< vs >0,55%) was not predictive of CR/CRp (86.6% n=39/45 vs 78.5% n=22/28, p=0.56). However, 2-year LFS (67.7+8% vs 30.1+10%, p=0.005) and 2-year OS (71.5+8% vs 30.1+10%, p=0.001). (Figure 1) were significantly higher for patients with low MDSC% (<0.55%). The incidence of cytologic relapse after achieving CR/CRp was significantly lower in these low MDSC% patients (12.8% n=5/39 vs 45.4% n=10/22, p=0.01). The median percentage of MDSC increased significantly between diagnosis (0,19%) and post-induction (0,84%; p=0.001). Median post-induction MDSC% were similar between patients achieving CR/CRp (0.9%, n=53 evaluable) vs others (0.44%, n=8 evaluable, p=0.34). No impact on relapse incidence nor on LFS and OS was observed when comparing patients based on the median post-induction level of MDSC and ROC curves did not identify thresholds able to predict LFS or OS using MDSC% post-induction. Multivariate analysis confirmed the independent prognostic value of MDCS% at diagnosis for AML patients (LFS p=0.026, HR 3.6, 95%CI 1.88-6.91; OS p=0.02-, HR 2.6, 95%CI 1.11-5.95) together with ELN 2017 classification (LFS p=0.0001, HR 2.34, 95%CI 1.10-4.97; OS p=0.01, HR 2.57, 95%CI 1.18-4.11). ALL: MDSC% at diagnosis were not predictive of response as 13/14 patients achieved CR/CRp after induction. The percentage of MDSC increased significantly between diagnosis (0.14%) and post- induction (0.97%; p=0.002). Again, this had no consequence on relapse incidence in CR/CRp patients nor on LFS and OS when comparing patients based on median post induction MDSC%. Discussion: This study evidenced that a higher percentage of peripheral monocytic MDSC at diagnosis predict lower survivals in AML patients because of more relapse. This result has to be confirmed on larger cohorts as it may implicate to propose immune intervention before or in combination with chemotherapy to improve these patients' outcome. Indeed, these cells seem to be an independent biomarker and potentially promising targets for the development of novel therapeutic strategies. Figure 1 Figure 1. Disclosures Moreau: Sanofi: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria.

P.158 Feeling Green

Background: Myeloid sarcoma (MS) is a rare solid tumour made of myeloblasts or immature myeloid cells in an extramedullary site or in bone, associated with systemic hematologic neoplasms. When they occur in the brain parenchyma, they can often be misdiagnosed. Methods: The authors report a case of a 4-year old boy 6 months out of remission from AML, presenting with a short history of headaches and vomiting, and found to have a heterogenous contrast-enhancing lesion in the right cerebellar hemisphere, with differential diagnosis of myeloid sarcoma, astrocytoma, medulloblastoma and ATRT. Preliminary diagnosis was made flow cytometry from an intraoperative biopsy. The patient had a long course of chemotherapy and radiation, but eventually died from the systemic burden of his AML. Results: The authors present a literature review on 178 published cases of CNS myeloid sarcomas, and their radiological presentation and the basis of immunohistochemical and pathological diagnosis is discussed. Conclusions: Diagnosis rests on a combination of immunohistochemistry and histopathology of biopsied tissue. Surgical resection is controversial, especially given the efficacy of chemotherapy and radiation, and prognosis remains unclear. As with all uncommon and rare clinical entities, further investigation is warranted to determine prognosis and optimal management of CNS myeloid sarcomas.