scholarly journals Immune Microenvironment Landscape in CNS Tumors and Role in Responses to Immunotherapy

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2032
Author(s):  
Hinda Najem ◽  
Mustafa Khasraw ◽  
Amy B. Heimberger
Keyword(s):  
Immune Cells ◽  
Hot Spots ◽  
Ex Vivo ◽  
Cns Tumors ◽  
Full Potential ◽  
Murine Models ◽  
Immune Microenvironment ◽  
Glioma Tissue ◽  
Clinical Benefits ◽  
Immune Profiling

Despite the important evolution of immunotherapeutic agents, brain tumors remain, in general, refractory to immune therapeutics. Recent discoveries have revealed that the glioma microenvironment includes a wide variety of immune cells in various states that play an important role in the process of tumorigenesis. Anti-tumor immune activity may be occurring or induced in immunogenic hot spots or at the invasive edge of central nervous system (CNS) tumors. Understanding the complex heterogeneity of the immune microenvironment in gliomas will likely be the key to unlocking the full potential of immunotherapeutic strategies. An essential consideration will be the induction of immunological effector responses in the setting of the numerous aspects of immunosuppression and evasion. As such, immune therapeutic combinations are a fundamental objective for clinical studies in gliomas. Through immune profiling conducted on immune competent murine models of glioma and ex vivo human glioma tissue, we will discuss how the frequency, distribution of immune cells within the microenvironment, and immune modulatory processes, may be therapeutically modulated to lead to clinical benefits.

scholarly journals PDTM-14. INTERACTIONS BETWEEN IMMUNE MICROENVIRONMENT, STEM CELLS, AND CELL PROLIFERATION IN PEDIATRIC EMBRYONAL CENTRAL NERVOUS SYSTEM [CNS] TUMORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi189-vi190
Author(s):  
Kristian Schafernak ◽  
Emma Utagawa ◽  
Shwetal Mehta ◽  
Tiffany Di Modica ◽  
Elliott Mufson ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Immune Cells ◽  
Cns Tumors ◽  
Stem Cell Marker ◽  
Proliferation Index ◽  
Cytotoxic T Cell ◽  
Cell Marker ◽  
Tumor Associated Macrophages ◽  
Immune Microenvironment

Abstract Mounting evidence suggests the brain’s own immune cells, microglia, and perivascular macrophages play important roles in immune surveillance/inflammation, but also support proliferation/growth of gliomas, possibly through interactions with tumor stem cells. Immune cells are increasingly regarded as potential targets for cancer therapy, however, the immune microenvironment has not been well-studied in pediatric embryonal CNS tumors. In a series of 13 medulloblastomas, 7 PNETs and 6 ATRTs, we quantified the number of cells immunopositive for macrophage/microglia Ionizing calcium binding adaptor molecule 1 [Iba1], CD68 (expressed on both “M1” antitumor/proinflammatory macrophages and “M2” protumor/anti-inflammatory macrophages), CD163 (“M2” macrophages), CD3 (T-cell marker), CD4 (helper T cell), CD8 (cytotoxic T cell) and CD20 (B-cell marker) and correlated these findings with the stem-cell marker nestin and the Ki67/MIB1 proliferation index. Significant results were as follows: Across groups, CD68 showed a strong Spearman rank-order correlation with both CD163 (r=0.610, p=0.0007) and nestin (r=0.577, p=0.0017), while CD3 correlated strongly with CD8 (r=0.601, p=0.004), CD4 (r=0.526, p=0.005) and CD20 (r=0.499, p=0.008). Between groups, the number of CD163-positive cells was significantly higher in PNETs compared to medulloblastomas (p=0.035). Within the medulloblastoma group, CD68 showed a significant relationship with nestin (r=0.595, p=0.0387) and Ki67 (r=0.606, p=0.0333), and there was a robust correlation between CD4 and CD8 values (r=0.846, p=0.0000002). Within PNETs, there was a strong negative correlation between CD163 and nestin (r=-0.883, p=0.0000002), while CD68 correlated with CD4 (r=0.803, p=0.006). Within ATRTs, nestin and Ki67 were strongly correlated (r=1.000, p=0.0028) as were CD68 and CD163 (r=0.943, p=0.017). These data suggest a role for blocking embryonal CNS tumor-associated macrophages by inhibiting the CSF1R pathway (perhaps in conjunction with CD8-positive T cells which could antagonize the immunosuppressive function of tumor-associated macrophages) or reprogramming them from an M2 to an M1 phenotype (particularly in PNETs, which had the highest number of CD163-positive cells).

Adoptive Cell Therapy for Gastrointestinal Cancers

2020 ◽  
Vol 04 (04) ◽  
pp. 345-350
Author(s):  
Ryan J. Slovak ◽  
Hyun S. Kim
Keyword(s):  
Cell Therapy ◽  
Clinical Research ◽  
Solid Tumors ◽  
Immune Cells ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Hematologic Malignancies ◽  
Gastrointestinal Cancers ◽  
Gastrointestinal Malignancies ◽  
Specific Antigens

AbstractThe reinfusion of autologous or allogeneic immune cells that have been educated and/or engineered ex vivo to respond to tumor-specific antigens is termed “adoptive cell therapy.” While adoptive cell therapy has made tremendous strides in the treatment of hematologic malignancies, its utilization for solid tumors has lagged somewhat behind. The purpose of this article is to concisely review the clinical research that has been done to investigate adoptive cell therapy as a treatment for gastrointestinal malignancies.

scholarly journals A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aubin Michalon ◽  
Andreas Hagenbuch ◽  
Christian Huy ◽  
Evita Varela ◽  
Benoit Combaluzier ◽  
...  
Keyword(s):  
Immune Cells ◽  
Ex Vivo ◽  
Phase 1 ◽  
Hereditary Disease ◽  
Elderly Subjects ◽  
Human Antibody ◽  
Cardiac Amyloid ◽  
Healthy Elderly ◽  
Ongoing Phase

AbstractTransthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.

scholarly journals Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2169
Author(s):  
Georgia Karpathiou ◽  
Maroa Dridi ◽  
Lila Krebs-Drouot ◽  
François Vassal ◽  
Emmanuel Jouanneau ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Positive Association ◽  
Immunohistochemical Analysis ◽  
Vascular Density ◽  
Immune Microenvironment ◽  
Significant Positive Association ◽  
Sequestosome 1 ◽  
Cell Expression

Chordomas are notably resistant to chemotherapy. One of the cytoprotective mechanisms implicated in chemoresistance is autophagy. There are indirect data that autophagy could be implicated in chordomas, but its presence has not been studied in chordoma tissues. Sixty-one (61) chordomas were immunohistochemically studied for autophagic markers and their expression was compared with the expression in notochords, clinicopathological data, as well as the tumor immune microenvironment. All chordomas strongly and diffusely expressed cytoplasmic p62 (sequestosome 1, SQSTM1/p62), whereas 16 (26.2%) tumors also showed nuclear p62 expression. LC3B (Microtubule-associated protein 1A/1B-light chain 3B) tumor cell expression was found in 44 (72.1%) tumors. Autophagy-related 16‑like 1 (ATG16L1) was also expressed by most tumors. All tumors expressed mannose-6-phosphate/insulin-like growth factor 2 receptor (M6PR/IGF2R). LC3B tumor cell expression was negatively associated with tumor size, while no other parameters, such as age, sex, localization, or survival, were associated with the immunohistochemical factors studied. LC3B immune cell expression showed a significant positive association with programmed death-ligand 1 (PD-L1)+ immune cells and with a higher vascular density. ATG16L1 expression was also positively associated with higher vascular density. Notochords (n = 5) showed different immunostaining with a very weak LC3B and M6PR expression, and no p62 expression. In contrast to normal notochords, autophagic factors such as LC3B and ATG16L1 are often present in chordomas, associated with a strong and diffuse expression of p62, suggesting a blocked autophagic flow. Furthermore, PD-L1+ immune cells also express LC3B, suggesting the need for further investigations between autophagy and the immune microenvironment.

scholarly journals Characterizing the Tumor Immune Microenvironment with Tyramide-Based Multiplex Immunofluorescence

2020 ◽  
Vol 25 (4) ◽  
pp. 417-432
Author(s):  
Hidetoshi Mori ◽  
Jennifer Bolen ◽  
Louis Schuetter ◽  
Pierre Massion ◽  
Clifford C. Hoyt ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Multispectral Imaging ◽  
Imaging System ◽  
Predictive Biomarkers ◽  
Cell Types ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Manual Processing ◽  
Cell Densities ◽  
Immune Profiling

AbstractMultiplex immunofluorescence (mIF) allows simultaneous antibody-based detection of multiple markers with a nuclear counterstain on a single tissue section. Recent studies have demonstrated that mIF is becoming an important tool for immune profiling the tumor microenvironment, further advancing our understanding of the interplay between cancer and the immune system, and identifying predictive biomarkers of response to immunotherapy. Expediting mIF discoveries is leading to improved diagnostic panels, whereas it is important that mIF protocols be standardized to facilitate their transition into clinical use. Manual processing of sections for mIF is time consuming and a potential source of variability across numerous samples. To increase reproducibility and throughput we demonstrate the use of an automated slide stainer for mIF incorporating tyramide signal amplification (TSA). We describe two panels aimed at characterizing the tumor immune microenvironment. Panel 1 included CD3, CD20, CD117, FOXP3, Ki67, pancytokeratins (CK), and DAPI, and Panel 2 included CD3, CD8, CD68, PD-1, PD-L1, CK, and DAPI. Primary antibodies were first tested by standard immunohistochemistry and single-plex IF, then multiplex panels were developed and images were obtained using a Vectra 3.0 multispectral imaging system. Various methods for image analysis (identifying cell types, determining cell densities, characterizing cell-cell associations) are outlined. These mIF protocols will be invaluable tools for immune profiling the tumor microenvironment.

scholarly journals The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment

2021 ◽  
Author(s):  
Wyatt M. Becicka ◽  
Peter Bielecki ◽  
Morgan Lorkowski ◽  
Taylor J. Moon ◽  
Yahan Zhang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Immunosuppressive Tumor Microenvironment

The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. To reprogram the tumor-resident innate immune cells, we developed an...

scholarly journals High copy number variations, particular transcription factors, and low immunity contribute to the stemness of prostate cancer cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zao Dai ◽  
Ping Liu
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Copy Number Variation ◽  
Cancer Cells ◽  
Immune Cells ◽  
Copy Number ◽  
Tumor Metastasis ◽  
Prostate Cancer Cells ◽  
Immune Microenvironment ◽  
Number Variation

Abstract Background Tumor metastasis is the main cause of death of cancer patients, and cancer stem cells (CSCs) is the basis of tumor metastasis. However, systematic analysis of the stemness of prostate cancer cells is still not abundant. In this study, we explore the effective factors related to the stemness of prostate cancer cells by comprehensively mining the multi-omics data from TCGA database. Methods Based on the prostate cancer transcriptome data in TCGA, gene expression modules that strongly relate to the stemness of prostate cancer cells are obtained with WGCNA and stemness scores. Copy number variation of stemness genes of prostate cancer is calculated and the difference of transcription factors between prostate cancer and normal tissues is evaluated by using CNV (copy number variation) data and ATAC-seq data. The protein interaction network of stemness genes in prostate cancer is constructed using the STRING database. Meanwhile, the correlation between stemness genes of prostate cancer and immune cells is analyzed. Results Prostate cancer with higher Gleason grade possesses higher cell stemness. The gene set highly related to prostate cancer stemness has higher CNV in prostate cancer samples than that in normal samples. Although the transcription factors of stemness genes have similar expressions, they have different contributions between normal and prostate cancer tissues; and particular transcription factors enhance the stemness of prostate cancer, such as PUM1, CLOCK, SP1, TCF12, and so on. In addition, the lower tumor immune microenvironment is conducive to the stemness of prostate cancer. CD8 + T cells and M1 macrophages may play more important role in the stemness of prostate cancer than other immune cells in the tumor microenvironment. Finally, EZH2 is found to play a central role in stemness genes and is negatively correlated with resting mast cells and positively correlated with activated memory CD4 + T cells. Conclusions Based on the systematic and combined analysis of multi-omics data, we find that high copy number variation, specific transcription factors, and low immune microenvironment jointly contribute to the stemness of prostate cancer cells. These findings may provide us new clues and directions for the future research on stemness of prostate cancer.

scholarly journals A novel application of bubble-eye strain of Carassius auratus for ex vivo fish immunological studies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroto Nakajima ◽  
Atsushi Miyashita ◽  
Hiroshi Hamamoto ◽  
Kazuhisa Sekimizu
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Ex Vivo ◽  
Large Bubble ◽  
Suitable Model ◽  
Bacterial Cells ◽  
Functional Impairments ◽  
Gene Expressions ◽  
Pro Inflammatory Cytokines

AbstractIn this study, we investigated a new application of bubble-eye goldfish (commercially available strain with large bubble-shaped eye sacs) for immunological studies in fishes utilizing the technical advantage of examining immune cells in the eye sac fluid ex vivo without sacrificing animals. As known in many aquatic species, the common goldfish strain showed an increased infection sensitivity at elevated temperature, which we demonstrate may be due to an immune impairment using the bubble-eye goldfish model. Injection of heat-killed bacterial cells into the eye sac resulted in an inflammatory symptom (surface reddening) and increased gene expression of pro-inflammatory cytokines observed in vivo, and elevated rearing temperature suppressed the induction of pro-inflammatory gene expressions. We further conducted ex vivo experiments using the immune cells harvested from the eye sac and found that the induced expression of pro-inflammatory cytokines was suppressed when we increased the temperature of ex vivo culture, suggesting that the temperature response of the eye-sac immune cells is a cell autonomous function. These results indicate that the bubble-eye goldfish is a suitable model for ex vivo investigation of fish immune cells and that the temperature-induced infection susceptibility in the goldfish may be due to functional impairments of immune cells.

IMMU-29. B-CELL-BASED VACCINE PRODUCES GLIOBLASTOMA-REACTIVE ANTIBODIES THAT CONTRIBUTE TO TUMOR CLEARANCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi98-vi98
Author(s):  
Brandyn Castro ◽  
Mark Dapash ◽  
David Hou ◽  
Aida Rashidi ◽  
Deepak Kanojia ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
Ex Vivo ◽  
Murine Models ◽  
Effector Functions ◽  
Tumor Bearing ◽  
Tumor Clearance ◽  
Cellular And Humoral Immunity

Abstract Glioblastomas (GBM) are characterized by a strong immunosuppressive environment, contributing to their poor prognosis and limited therapeutic response to immunotherapies. B-cells represent a unique opportunity to promote immunotherapy due to their potential to kill tumors by both cellular and humoral immunity. To generate our B-cell-based vaccine (BVax) platform, we activated 41BBL+ B cells from tumor bearing mice or GBM patient blood with BAFF, CD40, and IFNg. We have previously demonstrated that BVax potentiates radiation therapy, temozolomide and checkpoint blockade in murine models of GBM via enhancement of CD8+ T-cell based immunity. The aim of this current study is to evaluate the humoral effector functions of BVax. We examined the antibody (Ab) repertoire in vivo from serum of tumor-bearing B-cell knockout mice treated with BVax or by ex vivo stimulation of patient-derived BVax. Upon systemic administration, BVax infiltrates the tumor where it differentiates into plasmablasts. Murine BVax- and BNaive-derived serum immunoglobulin generated in vivo showed that the majority of murine BVax-derived Ab were IgG isotype, while BNaive mainly produced IgM isotype. Transfer of IgG from BVax treated mice directly into tumors of recipient animals significantly prolonged their survival, demonstrating anti-tumor cytotoxicity directly through humoral immunity. Patient-derived BVax activated ex vivo showed a plasmablast phenotype and the Ab repertoire supports the previous findings seen in our murine model. Our work suggests BVax-derived IgGs role in antibody-dependent cellular cytotoxicity and improved survival in murine models. This function, in addition to its role in cellular immunity against GBM, renders BVax a potentially effective alternative immunotherapeutic option for GBM patients.

Can Intratumoral neutrophil lymphocyte ratio (NLR) be a prognostic biomarker in breast cancer patients?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12573-e12573
Author(s):  
Yoshihisa Tokumaru ◽  
Masanori Oshi ◽  
Vijayashree Murthy ◽  
Eriko Katsuta ◽  
Nobuhisa Matsuhashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Immune Cells ◽  
Breast Cancer Patients ◽  
Immune Microenvironment ◽  
High Group ◽  
Anti Cancer ◽  
Tumor Immune Microenvironment ◽  
Er Positive

e12573 Background: In breast cancer patients, it is well known that the elevation of neutrophil lymphocyte ratio (NLR) in the blood are reported to associate with poor prognosis based on the notion that neutrophils represent pro-cancer, and lymphocytes represent anti-cancer immune cells. Tumor immune microenvironment has been demonstrated to play critical roles in the outcome of breast cancer patients. However, there is scarce evidence on the clinical relevance of intratumoral NLR in breast cancer patients. In the current study, we hypothesized that intratumoral NLR high tumors are associated with worse survival particularly in TNBC that is known to have high immune cell infiltration. Methods: A total of 1904 breast cancer patients’ data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) and analyzed. NLR was calculated by the gene expressions of CD66b (CEACAM8) and CD8 (CD8A). NLR high and low were divided by the median. Overall Survival (OS) and Disease-Free Survival were calculated utilizing Kaplan Meier method between intratumoral NLR high and low groups. xCell algorithm was used to analyze the infiltrated immune cells within the tumor immune microenvironment as we have previously published. Results: Intratumoral NLR high group was associated with worse OS in whole, ER-positive/HER2-negative, and triple negative (TN) subtypes, in agreement with the previous studies. TN subtype alone demonstrated worse DFS of NLR high group. Surprisingly, gene set enrichment analysis (GSEA) demonstrated no gene set enrichment to NLR high group, which implicates that there is no distinctive mechanism that associate with worse survival. Whereas, immune response-related gene sets significantly enriched to NLR low group in TN subtype. This enrichment was consistent in ER-positive/HER2-negative. Compared with ER-positive/HER2-negative subtype, anti-cancer immune cells such as CD4+ T cells, CD8+ T cells, M1 macrophage, and helper T helper type 1 cells were significantly infiltrated in TN patients (p < 0.001 for all genes), where M2 macrophages and neutrophils were less and regulatory T cells and T helper type 2 cells were more infiltrated in TN subtype. Furthermore, intratumoral NLR was significantly lower in TN compared with ER-positive/HER2-negative subtype (p < 0.001). These results suggest that intratumoral NLR low group is associated with better survival due to favorable tumor immune microenvironment in TN subtype rather than NLR high group has worse survival. Conclusions: Intratumoral NLR low tumor demonstrated more favorable OS and more favorable DFS in TN patients. Intratumoral NLR low breast cancer was associated with enhanced immune response and higher infiltration of anti-cancer immune cells were observed in TN subtype compared to ER-positive/HER2-negative which may contribute to the favorable outcome of in TN breast cancer.

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