scholarly journals IMMU-27. ANALYSIS OF IMMUNE SIGNATURES IN PEDIATRIC GLIOBLASTOMAS FOR PATIENT STRATIFICATION TO IMMUNOTHERAPY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii365-iii365
Author(s):  
Vidyalakshmi Chandramohan ◽  
Tyler Evangelous ◽  
Eric S Lipp ◽  
Bhavna Hora ◽  
Darell D Bigner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Cells ◽  
Immune Cells ◽  
Median Overall Survival ◽  
Immune Cell ◽  
Cell Mass ◽  
Cell Phenotype ◽  
Patient Stratification ◽  
Rna Seq ◽  
Selection Of

Abstract BACKGROUND Pediatric glioblastoma (pGBM), despite being relatively rare (incidence rate: 0.5/100,000), are a leading cause of cancer deaths in children with a median overall survival of 9–15 months. In recent years, immunotherapy has emerged as one of the more promising advances in oncology, with impressive response rates reported in several malignancies. Effective application of immunotherapy in brain tumors depends upon a better understanding of the immune cell phenotype and mechanisms of immunosuppression in these tumors. This understanding will allow for the selection of patient population who are most likely to benefit from immunotherapeutic approaches. MATERIAL AND METHODS In order to determine the frequency, distribution, and phenotype of tumor-infiltrating immune cells in pGBMs, we undertook an immunohistochemical survey on 19 recurrent pGBMs for CD3, CD8, CD4, CD163, PD-1, PD-L1, and FoxP3; RNA-Seq was also performed on a subset of 9 cases. Distribution of lymphocytes (LYMPHS) was recorded as intratumoral (IT) or perivascular (PV). RESULTS The analysis indicates intratumoral CD3+ LYMPHS are commonly <5% of tumor cell mass; however, approximately half (10/19) of these recurrent pGBM have infiltrates that range from 5 to 30% CD3+ LYMPHS. Of these, 4/10 CD3+ tumors exhibit brisk CD8+ infiltrates that are associated with PD-L1+ tumor cells. These tumors with brisk CD3+/CD8+ LYMPHS and PD-L1+ tumor cells were associated with longer survivals. The data were confirmed by RNA-seq analysis. CONCLUSION PD-L1+ pGBMs associated with CD3+/CD8+ LYMPH infiltrates deserve further investigation as candidates for immunotherapy.

scholarly journals 80 Cancer testis antigen burden: A novel predictive biomarker for immunotherapy in solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A89-A89
Author(s):  
Sarabjot Pabla ◽  
RJ Seager ◽  
Yong Hee Lee ◽  
Erik Van Roey ◽  
Shuang Gao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Regression Model ◽  
Tumor Cells ◽  
Immune Cell ◽  
Tumor Type ◽  
Cancer Testis Antigen ◽  
Rna Seq ◽  
Tumor Types ◽  
Cancer Testis

BackgroundWhen expressed in cancer cells, cancer testis antigens (CTAs) are highly immunogenic and have the capacity to elicit cancer-specific immune responses in diverse malignancies. With their expression limited to tumor cells, CTAs have become a prime target of natural T cell response, immune cell-based therapy, and cancer vaccines. In this study, we investigated CTA burden in real-world clinical tumors spanning multiple histologies, revealing a novel prognostic gene expression-based biomarker.MethodsTargeted RNA-seq was performed on 5450 FFPE tumors representing 39 histologic types, predominantly composed of lung cancer (40.4%) followed by colorectal cancer (10.6%) and breast cancer (8.6%). Using an amplicon-based NGS approach, expression levels of 17 CTA genes were ranked against a reference population. Cancer Testis Antigen Burden (CTAB) was calculated as the sum of the gene expression rank for each CTA gene. The median CTAB of ≥171 was used as cutoff for CTAB High versus Low classification. We estimated Pearson’s correlation for all CTA genes to discover co-expression patterns between CTAs and histologies. Overall survival (OS) analysis was performed using CoxPh regression model whereas response analysis was performed using logistic regression model with p-values reported.ResultsWithin the tumor samples, CTAB values ranged from 0–1700, with kidney cancer demonstrating overall lowest mean CTAB (110) and melanoma the highest (550). NSCLC had an average CTAB of 283. In an immune checkpoint blockade treated retrospective cohort of 110 NSCLC patients, High CTAB showed better OS compared to Low CTA (HR: 0.55, p=0.07). Additionally, when combined with tumor inflammation and cell proliferation biomarkers, highly inflamed but poorly proliferative tumors with High CTAB had improved OS (HR: 0.27, p=0.05). No significant association with response was detectedConclusionsOur studies show that co-expression of multiple CTA genes occurs in many tumor types and can be reliably detected using a targeted RNA-seq approach. Utilization of this co-expression pattern to calculate CTAB reveals tumor-type associated signatures, which in a small NSCLC cohort is associated with the overall survival. The findings suggest that these immunogenic antigens expose the tumor cells to natural or immunotherapy augmented cell-based immune response, and that CTAB is a potential predictive marker for therapeutic response to checkpoint inhibitors. Further studies are needed to establish the predictive value in other tumor types, as well as the role of CTAB in immune cell therapies and vaccinations.

scholarly journals Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages

Metabolites ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 372 ◽  
Author(s):  
Karl J. Harber ◽  
Kyra E. de Goede ◽  
Sanne G. S. Verberk ◽  
Elisa Meinster ◽  
Helga E. de Vries ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cell Phenotype ◽  
Independent Manner ◽  
Inflammatory Macrophages ◽  
Necrosis Factor

Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

scholarly journals Diverse homeostatic and immunomodulatory roles of immune cells in the developing mouse lung at single cell resolution

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Racquel Domingo-Gonzalez ◽  
Fabio Zanini ◽  
Xibing Che ◽  
Min Liu ◽  
Robert C Jones ◽  
...  
Keyword(s):  
Postnatal Development ◽  
Immune Cells ◽  
Immune Cell ◽  
Mouse Lung ◽  
Cell Phenotype ◽  
Physical Interaction ◽  
Early Postnatal Development ◽  
Hypoxic Environment ◽  
Context Specific ◽  
Air Liquid Interface

At birth, the lungs rapidly transition from a pathogen-free, hypoxic environment to a pathogen-rich, rhythmically distended air-liquid interface. Although many studies have focused on the adult lung, the perinatal lung remains unexplored. Here, we present an atlas of the murine lung immune compartment during early postnatal development. We show that the late embryonic lung is dominated by specialized proliferative macrophages with a surprising physical interaction with the developing vasculature. These macrophages disappear after birth and are replaced by a dynamic mixture of macrophage subtypes, dendritic cells, granulocytes, and lymphocytes. Detailed characterization of macrophage diversity revealed an orchestration of distinct subpopulations across postnatal development to fill context-specific functions in tissue remodeling, angiogenesis, and immunity. These data both broaden the putative roles for immune cells in the developing lung and provide a framework for understanding how external insults alter immune cell phenotype during a period of rapid lung growth and heightened vulnerability.

scholarly journals Immune Cell Profiling of Peripheral Blood as Signature for Response During Checkpoint Inhibition Across Cancer Types

2021 ◽  
Vol 11 ◽  
Author(s):  
Vinicius Araujo B. de Lima ◽  
Morten Hansen ◽  
Iben Spanggaard ◽  
Kristoffer Rohrberg ◽  
Sine Reker Hadrup ◽  
...  
Keyword(s):  
Immune Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Large Fraction ◽  
Response To Treatment ◽  
Cell Phenotype ◽  
Checkpoint Inhibition ◽  
Color Flow ◽  
Immune Profile

Despite encouraging results with immune checkpoint inhibition (ICI), a large fraction of cancer patients still does not achieve clinical benefit. Finding predictive markers in the complexity of the tumor microenvironment is a challenging task and often requires invasive procedures. In our study, we looked for putative variables related to treatment benefit among immune cells in peripheral blood across different tumor types treated with ICIs. For that, we included 33 patients with different solid tumors referred to our clinical unit for ICI. Peripheral blood mononuclear cells were isolated at baseline, 6 and 20 weeks after treatment start. Characterization of immune cells was carried out by multi-color flow cytometry. Response to treatment was assessed radiologically by RECIST 1.1. Clinical outcome correlated with a shift towards an effector-like T cell phenotype, PD-1 expression by CD8+T cells, low levels of myeloid-derived suppressor cells and classical monocytes. Dendritic cells seemed also to play a role in terms of survival. From these findings, we hypothesized that patients responding to ICI had already at baseline an immune profile, here called ‘favorable immune periphery’, providing a higher chance of benefitting from ICI. We elaborated an index comprising cell types mentioned above. This signature correlated positively with the likelihood of benefiting from the treatment and ultimately with longer survival. Our study illustrates that patients responding to ICI seem to have a pre-existing immune profile in peripheral blood that favors good outcome. Exploring this signature can help to identify patients likely to achieve benefit from ICI.

scholarly journals HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i22-i22
Author(s):  
John DeSisto ◽  
Andrew Donson ◽  
Rui Fu ◽  
Bridget Sanford ◽  
Kent Riemondy ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Modalities ◽  
Patient Specific ◽  
Cell Populations ◽  
High Grade ◽  
Methylation Data ◽  
Rna Seq

Abstract Background Pediatric high-grade glioma (PHGG) is a deadly childhood brain tumor that responds poorly to treatment. PHGG comprises two major subtypes: cortical tumors with wild-type H3K27 and diffuse midline gliomas (DMG) that occur in the midline and have characteristic H3K27M mutations. Cortical PHGG is heterogeneous with multiple molecular subtypes. In order to identify underlying commonalities in cortical PHGG that might lead to better treatment modalities, we performed molecular profiling, including single-cell RNA-Seq (scRNA-Seq), on PHGG samples from Children’s Hospital Colorado. Methods Nineteen cortical PHGG tumor samples, one DMG and one normal margin sample obtained at biopsy were disaggregated to isolate viable cells. Fifteen were glioblastomas (GBM), including five with epithelioid and/or giant cell features and five radiation-induced glioblastomas (RIG). There were also four non-GBM PHGG. We performed scRNA-Seq using 10X Genomics v.3 library preparation to enable capture of infiltrating immune cells. We also performed bulk RNA-Seq and DNA methylation profiling. Results After eliminating patient-specific and cell-cycle effects, RIG, epithelioid GBM, and other GBM each formed identifiable subgroups in bulk RNA-Seq and scRNA-Seq datasets. In the scRNA-Seq data, clusters with cells from multiple tumor samples included a PDGFRA-positive population expressing oligodendrocyte progenitor markers, astrocytic, mesenchymal and stemlike populations, macrophage/monocyte immune cells, and a smaller T-cell population. Analyses of DNA methylation data showed PDGFRA and CDK4 amplification and CDKN2A deletion are common alterations among PHGG. Inferred copy number variation analysis of the single-cell data confirmed that individual tumors include populations that both include and lack the molecular alterations identified in the methylation data. RNA velocity studies to define tumor cells of origin and further analyses of the immune cell populations are underway. Conclusions Single-cell analysis of PHGG confirms a large degree of tumor heterogeneity but also shows that PHGG have stemlike, mesenchymal and immune cell populations with common characteristics.

Clinicopathological and prognostic significance of microsatellit instability (MSI) status and PDl-1 expression in Turkish patients with gastric cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15538-e15538
Author(s):  
Ibrahim Yildiz ◽  
Seyma Bahsi ◽  
Sibel Erdamar ◽  
Suha Goksel ◽  
Gokhan Demir ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Microsatellite Instability ◽  
Tumor Cells ◽  
Immune Cells ◽  
Prognostic Significance ◽  
Rational Approach ◽  
Preoperative Treatment ◽  
Gastric Cancer Patients ◽  
The Impact

e15538 Background: The aim of this study was to evaluate the prognostic role of microsatellite instability (MSI) status and PD-L1 expression in surgically resected gastric cancer and the relationship of these parameters with clinicopathological features. Methods: Eighty six gastric cancer patients which had curative surgical resection at Acibadem Atakent and Maslak Hospitals between 2010 and 2017 were analysed. Tumor samples were evaluated with MSI and PD-L1 antibodies by immunohistochemical (IHC) methods. PD-L1 IHC scoring was performed using the combined positive score (CPS). Survival analysis was accomplished using the Kaplan-Meier method. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival. Results: The rate of PD-L1 expression in tumor cells was 34.9% (n = 30) and the frequency of PD-L1 expression in immune cells with CPS (≥1%) was 57% (n = 49). MSI-H was detected in 11.6%(n = 10), and more observed in PD-L1 positive cases (p = 0.021). MSI-H status was significantly correlated with older age, increased tumor size, presence of PD-L1 expression, and adenocarcinoma subtype. PD-L1 expression was associated with lymph node metastasis, adenocarcinoma subtype, microsatellite instability, presence of preoperative treatment and improved response to preoperative chemotherapy. In our study, the impact of MSI status on survival was not demonstrated, but PD-L1 expression positivity(≥1%) in both tumor cells (15.7 vs 53.4 months, p = 0.008)and in immune cells (20.4 vs NR; p = 0.027) was associated with short overall survival. PD -L1 expression in tumor cells was an independent prognostic factor for overall survival in multivariate analysis (HR: 2.28, p = 0.047). Conclusions: PD-L1 expression was related to a poor prognosis in patients with gastric cancer and can represent a rational approach for PD-1/PD-L pathway-targeted immunotherapy.

Magrolimab + azacitidine versus azacitidine + placebo in untreated higher risk (HR) myelodysplastic syndrome (MDS): The phase 3, randomized, ENHANCE study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS7055-TPS7055
Author(s):  
Guillermo Garcia-Manero ◽  
Naval Guastad Daver ◽  
Jin Xu ◽  
Mark Chao ◽  
Trisha Chung ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Tumor Cells ◽  
Immune Cell ◽  
Residual Disease ◽  
Unmet Need ◽  
International Prognostic Scoring System ◽  
Phase 3 ◽  
Patient Reported ◽  
Very High

TPS7055 Background: MDS is a clonal myeloid disorder characterized by cytopenia and ineffective hematopoiesis. The median age of diagnosis is approximately 70 yrs of age and prognosis and treatment are guided by the Revised International Prognostic Scoring System (IPSS-R) criteria. Patients with intermediate, high and very high risk MDS (HR-MDS) have a median overall survival (OS) of 0.8 to 3.7 years. Despite the high unmet need in this patient population, azacitidine (AZA) is the only approved therapy for HR-MDS which has improved overall survival in clinical trials to date. However, these agents lead to low complete response (CR) rates (10-17%) with limited OS ( = 2 years), indicating a need for alternative therapy. Magrolimab is a first-in-class monoclonal antibody that blocks the macrophage inhibitory immune checkpoint CD47, a “do not eat me” signal overexpressed on tumor cells. Binding of magrolimab to CD47 leads to phagocytosis of tumor cells. AZA increases expression of prophagocytic “eat me” signals, facilitating synergy with magrolimab. In an ongoing phase 1b study, the combination of magrolimab + AZA led to high response rates (ORR 91%, with a CR of 42%) and an acceptable safety profile without significant immune-related adverse events. ENHANCE (NCT04313881) is a phase 3 trial comparing the efficacy and safety of magrolimab + AZA with that of AZA + placebo (PBO) in previously untreated patients with HR-MDS. Methods: Patients ≥18 years old with previously untreated intermediate to very high risk MDS by IPSS-R are eligible for ENHANCE. Randomization is 1:1 to magrolimab + AZA or AZA + PBO with no crossover allowed. Magrolimab or placebo is administered intravenously (IV) with an initial 1 mg/kg priming dose to mitigate on target anemia. An intrapatient dose escalation regimen up to 30 mg/kg is then administered through Cycle 1, 30 mg/kg weekly dosing in Cycle 2, with 30 mg/kg Q2W dosing occurring in Cycle 3 and beyond. AZA is administered per regional prescribing information. Patients may remain on treatment until disease progression, relapse, loss of clinical benefit, or until unacceptable toxicities occur. Two primary efficacy endpoints are CR rate and OS. For patients undergoing allogeneic stem cell transplantation (ASCT), data for the CR rate will be censored at the time of ASCT and OS will be censored at the last known alive date. Secondary efficacy endpoints include RBC transfusion independence rate, event-free survival, minimal residual disease-negative rate, time to AML transformation, and patient-reported Functional Assessment of Cancer Therapy (FACT)-Anemia response rate. Biomarkers of immune cell recruitment, immune cell signaling, and bone marrow penetration of magrolimab will also be explored. Planned enrollment is approximately 520 patients globally, which began in September 2020. Accrual is ongoing. Clinical trial information: NCT04313881.

scholarly journals LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000552 ◽  
Author(s):  
Niklas Klümper ◽  
Damian J Ralser ◽  
Emma Grace Bawden ◽  
Jenny Landsberg ◽  
Romina Zarbl ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Cell Lines ◽  
Immune Cells ◽  
Immune Cell ◽  
Clear Cell ◽  
Immune Cell Infiltration ◽  
Strongly Correlated ◽  
Cell Renal Cell Carcinoma ◽  
Immune Cell Infiltrates

BackgroundLymphocyte activating 3 (LAG3, LAG-3, CD223) is a promising target for immune checkpoint inhibition in clear cell renal cell carcinoma (KIRC). The aim of this study was to investigate the epigenetic regulation ofLAG3in KIRC by methylation.MethodsWe correlated quantitativeLAG3methylation levels with transcriptional activity, immune cell infiltration, and overall survival in a cohort of n=533 patients with KIRC and n=160 normal adjacent tissue (NAT) samples obtained from The Cancer Genome Atlas (TCGA). Furthermore, we analyzedLAG3methylation in peripheral blood mononuclear cells (PBMCs) and KIRC cell lines. We validated correlations between LAG3 expression, immune cell infiltrates, survival, and methylation in an independent KIRC cohort (University Hospital Bonn (UHB) cohort, n=118) by means of immunohistochemistry and quantitative methylation-specific PCR.ResultsWe found differential methylation profiles among PBMCs, NAT, KIRC cell lines, and KIRC tumor tissue. Methylation strongly correlated with LAG3 mRNA expression in KIRCs (TCGA cohort) and KIRC cell lines. In the UHB cohort, methylation correlated with LAG3-positive immune cells and tumor-intrinsic LAG3 protein expression. Furthermore,LAG3methylation strongly correlated with signatures of distinct immune cell infiltrates, an interferon-y signature (TCGA cohort), and immunohistochemically quantified CD45+, CD8+, and CD4+immune cell infiltrates (UHB cohort). LAG3 mRNA expression (TCGA cohort), methylation (both cohorts), and tumor cell-intrinsic protein expression (UHB cohort) was significantly associated with overall survival.ConclusionOur data suggest an epigenetic regulation of LAG3 expression in tumor and immune cells via DNA methylation. LAG3 expression and methylation is associated with a subset of KIRCs showing a distinct clinical course and immunogenicity. Our study provides rationale for further testingLAG3DNA methylation as a predictive biomarker for response to LAG3 immune checkpoint inhibitors.

The role of SLAM family receptors in immune cell signalingThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 832-843 ◽  
Author(s):  
Elena A. Ostrakhovitch ◽  
Shawn S.-C. Li
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Types ◽  
Health And Disease ◽  
Slam Family ◽  
Different Cell Types ◽  
Selection Of

The signaling lymphocyte-activating molecule (SLAM) family immunoreceptors are expressed in a wide array of immune cells, including both T and B lymphocytes. By virtue of their ability to transduce tyrosine phosphorylation signals through the so-called ITSM (immunoreceptor tyrosine-based switch motif) sequences, they play an important part in regulating both innate and adaptive immune responses. The critical role of the SLAM immunoreceptors in mediating normal immune reactions was highlighted in recent findings that SAP, a SLAM-associated protein, modulates the activities of various immune cells through interactions with different members of the SLAM family expressed in these cells. Importantly, mutations or deletions of the sap gene in humans result in the X-linked lymphoproliferative syndrome. In this review, we summarize current knowledge and survey the latest developments in signal transduction events triggered by the activation of SLAM family receptors in different cell types.

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