Deciphering the Labyrinthine System of the Immune Microenvironment in Recurrent Glioblastoma: Recent Original Advances and Lessons from Clinical Immunotherapeutic Approaches

The interpretation of the presence and function of immune infiltration in glioblastoma (GBM) is still debated. Over the years, GBM has been considered a cold tumor that is less infiltrated by effector cells and characterized by a high proportion of immunosuppressive innate immune cells, including GBM-associated microglia/macrophages (GAMs). In this context, the failure of checkpoint inhibitors, particularly in recurrent GBM (rGBM), caused us to look beyond the clinical results and consider the point of view of immune cells. The tumor microenvironment in rGBM can be particularly hostile, even when exposed to standard immunomodulatory therapies, and tumor-infiltrating lymphocytes (TILs), when present, are either dysfunctional or terminally exhausted. However, after checkpoint blockade therapy, it was possible to observe specific recruitment of adaptive immune cells and an efficient systemic immune response. In this review article, we attempt to address current knowledge regarding the tumor and immune microenvironment in rGBM. Furthermore, immunosuppression induced by GAMs and TIL dysfunction was revisited to account for genetic defects that can determine resistance to therapies and manipulate the immune microenvironment upon recurrence. Accordingly, we reevaluated the microenvironment of some of our rGBM patients treated with dendritic cell immunotherapy, with the goal of identifying predictive immune indicators of better treatment response.

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Hematopoietic Stem and Immune Cells in Chronic HIV Infection

Stem Cells International ◽

10.1155/2015/148064 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Jielin Zhang ◽

Clyde Crumpacker

Keyword(s):

Hiv Infection ◽

Immune Cells ◽

Memory Cell ◽

Point Of View ◽

Immune Memory ◽

Self Renewal ◽

Viral Pathogen ◽

Hematopoietic Stem ◽

Effector Cells ◽

Chronic Hiv Infection

Hematopoietic stem cell (HSC) belongs to multipotent adult somatic stem cells. A single HSC can reconstitute the entire blood system via self-renewal, differentiation into all lineages of blood cells, and replenishment of cells lost due to attrition or disease in a person’s lifetime. Although all blood and immune cells derive from HSC, immune cells, specifically immune memory cells, have the properties of HSC on self-renewal and differentiation into lineage effector cells responding to the invading pathogens. Moreover, the interplay between immune memory cell and viral pathogen determines the course of a viral infection. Here, we state our point of view on the role of blood stem and progenitor cell in chronic HIV infection, with a focus on memory CD4 T-cell in the context of HIV/AIDS eradication and cure.

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Stromal characterization of small bowel adenocarcinomas.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.288 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 288-288

Author(s):

Katrina Pedersen ◽

Thomas C. Smyrk ◽

Robert R. McWilliams

Keyword(s):

Small Bowel ◽

T Lymphocytes ◽

Immune Cells ◽

Checkpoint Inhibitors ◽

Membrane Integrity ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Stroma ◽

Cd8 Cells ◽

Tumor Types ◽

E Cadherin

288 Background: Programmed-death 1 (PD-1) receptor and its corresponding ligand, PD-L1, have been found to be clinically relevant in maintaining immune tolerance to malignant cells in an increasing number of tumor types. We have previously shown that nearly half of 48 randomly selected, resected small bowel adenocarcinomas at any stage exhibit positive PD-L1 expression. Furthermore, a larger quantity of tumor infiltrating lymphocytes (TILs) within the tumor stroma or microsatellite instability (MSI-H) have been associated with improved likelihood of response to PD-1 and PD-L1 inhibitors. We have descriptively characterized the stromal components of small bowel adenocarcinomas to determine if similar tumor/stromal features to drug-responsive tumors can be seen. Methods: 30 tumors were immunohistochemically stained for CD8 (T-lymphocytes), CD68 (macrophages), and e-cadherin. They were morphologically screened for MSI-H status with light microscopy. PD-L1 staining was previously performed and reported. Results: Of the 30 tumors, there was no correlation between the density of macrophages and T-lymphocytes, nor was there a correlation with the burden of immune cells with e-cadherin expression. 14/30 (47%) tumors had 3+/4+ expression of CD8+ lymphocytes. 7/14 (50%) of these tumors were morphologically MSI-H. No tumors with low CD8+ cells (1+/2+) were MSI-H. PD-L1 expression colocalized exclusively with macrophages and not with lymphocytes. Conclusions: There appears to be no association between the proportions of immune cells and basement membrane integrity. MSI-H tumors are more likely to have a greater quantity of CD8+ lymphocytes in the stroma; however, PD-L1 stromal expression appears to colocalize with macrophages. Further pathologic characterization is needed in patients treated with PD-1 and other immune checkpoint inhibitors to determine the clinical significance of these observations.

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Immune Response to SARS-CoV-2 Infection

International Journal of Current Science Research and Review ◽

10.47191/ijcsrr/v3-i10-03 ◽

2020 ◽

Vol 03 (10) ◽

Author(s):

Dr. Ahmed Al-Shukaili ◽

Keyword(s):

Immune Response ◽

Immune System ◽

Severe Acute Respiratory Syndrome ◽

Global Health ◽

Immune Cells ◽

Current Knowledge ◽

Adaptive Immune ◽

Proinflammatory Mediators ◽

Adaptive Immune Cells ◽

New Type

In December 2019 a new type of coronaviruses appeared in China and named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the disease associated with this virus is called Coronavirus Disease 2019 or COVID-19. Currently, COVID19 is the main global health threat. In this review, we focus in the current knowledge of immune response to SARS-CoV-2. Dysregulation of immune system, such as elevation levels of proinflammatory mediators and their roles in disease progression and pathogenesis as well as imbalance between innate and adaptive immune cells, are discussed in this review.

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Potential therapeutic target for PD1/PDL1 blockade in microsatellite medullary carcinomas based on PDL1 expression by tumor cells and infiltration by numerous PD1+ T lymphocytes.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14599 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14599-e14599

Author(s):

Celine Bossard ◽

Eva Ott ◽

Delphine Dansette ◽

Adrien Ouary ◽

Anne Jarry ◽

...

Keyword(s):

Tumor Cells ◽

Immune Cells ◽

Significant Proportion ◽

Tumor Infiltrating Lymphocytes ◽

Point Of View ◽

Potential Therapeutic Target ◽

Preferential Expression ◽

Tissue Sections ◽

Clinical Point ◽

Infiltrating Lymphocytes

e14599 Background: PD1/PDL1 blockade showed therapeutic efficacy in only microsatellite (MSI) colorectal carcinomas (CRC), however, the profile of PDL1 and PD1 expression in CRC is only partially described. Methods: We thus analyzed on FFPE whole-tissue sections of 80 CRC, the expression profile of PDL1 by tumor and/or immune cells by immunohistochemistry (clone E1L3N) depending on the MSI status and the histological subtype, and correlated to the density of PD1+ and Tbet+ (able to secrete IFNg known to induce PDL1) tumor-infiltrating lymphocytes (TIL). Results: 78% of MSI CRC (32/41) overexpressed PDL1 either by tumor or immune cells versus 46% of MSS CRC (18/39) (p 0.005). This overexpression was heterogeneous within the same tumor in most of cases. Among MSI CRC, PDL1 was preferentially overexpressed in medullary carcinomas (MC, 19/21, 90%) compared with 65% (13/20) in non medullary adenocarcinomas (p 0.06). PDL1 expression by tumor cells was only observed in MSI CRC (19/41, 46% with PDL1 expression in more than 5% of tumor cells – score 1), and preferentially in MC (57% vs 5% in no medullary adenocarcinomas, with PDL1 expression in more than 50% of tumor cells – score 3, p 0.0005). Conversely, PDL1 expression by immune cells was observed in MSI CRC (23/41, 56% with PDL1 expression by more than 5 sheets of 50 positive cells) but also in MSS CRC (18/39, 43%) (p 0.5). The density of PD1+ cells was significantly correlated to the PDL1 expression, as well as the density of Tbet+ TIL. Conclusions: PDL1 expression is 1) heterogeneous in CRC, among CRC but also within the same tumor, 2) preferentially observed in MSI CRC (78%), especially in MC (90%), where PDL1 is expressed by tumor cells, 3) correlated with the density of PD1+ or Tbet+ TIL, and 4) observed in a significant proportion of MSS CRC (46%) by immune cells only. From a clinical point of view, PDL1 expression has to be determined at best in full tissue section and besides its preferential expression in MSI CRC, its significant frequency and expression profil (only by immune cells) in MSS CRC should be taken into account in the future clinical trials testing the efficacy of anti-PD1/PDL1 antibodies.

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Association of Th2 high tumors with aggressive features of breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e12584 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e12584-e12584

Author(s):

Yoshihisa Tokumaru ◽

Lan Le ◽

Masanori Oshi ◽

Eriko Katsuta ◽

Nobuhisa Matsuhashi ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Progression ◽

Immune Cells ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Th2 Cells ◽

Immune Microenvironment ◽

Adaptive Immune Cells ◽

Tumor Immune Microenvironment

e12584 Background: Recent studies have shown that infiltrating T-lymphocytes have been implicated in the promotion of breast cancer progression. Upon activation, these antigen-presenting cells then recruit adaptive immune cells. It has been proposed that polarization of CD4+ effector T-cells towards the immunosuppressive Th2 cells induce cytokine release and T-cell anergy, which lead to polarization of M2 tumor-associated macrophages (TAM’s), providing a protumorigenic microenvironment. We hypothesized that there is a correlation between high levels of Th2 cells and aggressive features of breast cancer and unfavorable tumor immune environment. Methods: Clinicopathological data and overall survival information was obtained on 1069 breast cancer patients from The Cancer Genome Atlas (TCGA) database. We defined Th2 high and low levels with the median cutoff. Results: Analysis of cell composition of the immune cells within tumor immune microenvironment demonstrated that Th2 high tumors did not consistently associated with unfavorable tumor immune microenvironment. Pro-cancer immune cells, such as macrophage M2 cells were increased with Th2 high tumors whereas, regulatory T cells were decreased with Th2 high tumors (p < 0.01 and p < 0.001 respectively). On the contrary, infiltration of anti-cancer cells, such as macrophage M1 was increased whereas CD8 T cells were decreased with Th2 high tumors (p < 0.05 and p < 0.001 respectively). Th2 was not shown to have correlation with IL-4, IL-6, IL-10 and IL-13, all of which has been reported to associate with Th2 cells. Th2 levels were associated with advanced grades. Also, correlation analysis demonstrated that there was a strong correlation between Th2 levels and Ki-67. These results were further validated with gene set enrichment analysis (GSEA). GSEA revealed that in Th2 high tumors enriched the gene sets associated with cell proliferation and cell cycle. Conclusions: High expression of immunosuppressive Th2 cells was associated with highly proliferative features of breast cancer, but not with unfavorable tumor immune microenvironment.

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The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

Cancers ◽

10.3390/cancers13010134 ◽

2021 ◽

Vol 13 (1) ◽

pp. 134

Author(s):

Anastasia Mpakali ◽

Efstratios Stratikos

Keyword(s):

Immune Checkpoint ◽

Antigen Processing ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Clinical Results ◽

Therapeutic Benefit ◽

Complementary Approach ◽

Intracellular Antigen ◽

Antigen Processing And Presentation

Recent clinical successes of cancer immunotherapy using immune checkpoint inhibitors (ICIs) are rapidly changing the landscape of cancer treatment. Regardless of initial impressive clinical results though, the therapeutic benefit of ICIs appears to be limited to a subset of patients and tumor types. Recent analyses have revealed that the potency of ICI therapies depends on the efficient presentation of tumor-specific antigens by cancer cells and professional antigen presenting cells. Here, we review current knowledge on the role of antigen presentation in cancer. We focus on intracellular antigen processing and presentation by Major Histocompatibility class I (MHCI) molecules and how it can affect cancer immune evasion. Finally, we discuss the pharmacological tractability of manipulating intracellular antigen processing as a complementary approach to enhance tumor immunogenicity and the effectiveness of ICI immunotherapy.

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Statistical framework for studying the spatial architecture of the tumor immune microenvironment

10.1101/2021.04.27.21256104 ◽

2021 ◽

Author(s):

Christopher Wilson ◽

Ram Thapa ◽

Jordan Creed ◽

Jonathan Nguyen ◽

Carlos Moran Segura ◽

...

Keyword(s):

Overall Survival ◽

T Cells ◽

Immune Cells ◽

Spatial Clustering ◽

Cytotoxic T Cells ◽

Tumor Infiltrating Lymphocytes ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Infiltrating Lymphocytes ◽

Spatial Architecture

AbstractNew technologies, such as multiplex immunofluorescence microscopy (mIF), are being developed and used for the assessment and visualization of the tumor immune microenvironment (TIME). These assays produce not only an estimate of the abundance of immune cells in the TIME, but also their spatial locations; however, there are currently few approaches to analyze the spatial context of the TIME. Thus, we have developed a framework for the spatial analysis of the TIME using Ripley’s K, coupled with a permutation-based framework to estimate and measure the departure from complete spatial randomness (CSR) as a measure of the interactions between immune cells. This approach was then applied to ovarian cancer using mIF collected on intra-tumoral regions of interest (ROIs) and tissue microarrays (TMAs) from 158 high-grade serous ovarian carcinoma patients in the African American Cancer Epidemiology Study (AACES) (94 subjects on TMAs resulting in 259 tissue cores; 91 subjects with 254 ROIs). Cox proportional hazard models were constructed to determine the association of abundance and spatial clustering of tumor-infiltrating lymphocytes, cytotoxic T-cells, and regulatory T-cells, and overall survival. We found that EOC patients with high abundance and low spatial clustering of tumor-infiltrating lymphocytes and cytotoxic T-cells in their tumors had the best overall survival. In contrast, patients with low levels of regulatory T-cells but with a high level of spatial clustering (compare to those with a low level of spatial clustering) had better survival. These findings underscore the prognostic importance of evaluating not only immune cell abundance but also the spatial contexture of the immune cells in the TIME. In conclusion, the application of this spatial analysis framework to the study of the TIME could lead to the identification of immune content and spatial architecture that could aid in the determination of patients that are likely to respond to immunotherapies.

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Discrete immune response signature to SARS-CoV-2 mRNA vaccination versus infection

10.1101/2021.04.20.21255677 ◽

2021 ◽

Author(s):

Ellie N. Ivanova ◽

Joseph C. Devlin ◽

Terkild B. Buus ◽

Akiko Koide ◽

Amber Cornelius ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Immune Cells ◽

Transcriptional Profiling ◽

Cell Receptor ◽

Interferon Response ◽

Effector Cells ◽

Adaptive Immune ◽

Adaptive Immune Cells

AbstractBoth SARS-CoV-2 infection and vaccination elicit potent immune responses. A number of studies have described immune responses to SARS-CoV-2 infection. However, beyond antibody production, immune responses to COVID-19 vaccines remain largely uncharacterized. Here, we performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine. Phenotypic and transcriptional profiling of immune cells, coupled with reconstruction of the B and T cell antigen receptor rearrangement of individual lymphocytes, enabled us to characterize and compare the host responses to the virus and to defined viral antigens. While both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells. Importantly, the divergence in immune subsets engaged, the transcriptional differences in key immune populations, and the differences in maturation of adaptive immune cells revealed by our analysis have far-ranging implications for immunity to this novel pathogen.

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Modulation of T cell and macrophage tumor infiltration by the TLR9 agonist lefitolimod in a murine model of colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.687 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 687-687

Author(s):

Manuel Schmidt ◽

Detlef Oswald ◽

Barbara Volz ◽

Burghardt Wittig ◽

Kerstin Kapp

Keyword(s):

T Cells ◽

T Cell ◽

Immune Cells ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Immune Surveillance ◽

Adaptive Immune System ◽

Intratumoral Injection ◽

Effector Cells ◽

T Cell Infiltration

687 Background: The use of TLR9 agonists for immunotherapeutic approaches is supported by preclinical and ongoing clinical studies. Lefitolimod, a covalently-closed dumbbell-shaped DNA construct, is an immune surveillance reactivator which broadly activates cells of the innate and adaptive immune system. The conversion of non-immunogenic (cold) tumors into immunogenic (hot) tumors, characterized by their T-cell infiltration, is a pre-requisite for response to immunotherapies. By its mode-of-action lefitolimod likely provides the necessary signals for activation of immune cells and their differentiation into anti-tumor effector cells as well as their recruitment to the tumor microenvironment (TME). Methods: To support the further clinical development of lefitolimod in mCRC, the syngeneic colon carcinoma model CT26 was used to evaluate anti-tumoral efficacy of lefitolimod and its modulation of the TME. The phenotype of T cells and macrophages present within tumor-infiltrating immune cells were analyzed by flow cytometry. Their localization within the tumor was investigated by immunohistochemistry. Results: Intratumoral injection of single-agent lefitolimod in the CT26 model resulted in reduced tumor growth. This was accompanied by an increased infiltration of T cells, in particular CD8+ T cells, into the tumor center. The CD8+ T cells were activated and showed an up-regulation of the cytolytic effector Granzyme B. Correspondingly, the ratio of activated CD8+ T cells with cytolytic function to regulatory T cells was increased by lefitolimod. Moreover, lefitolimod led to the recruitment of macrophages into the tumor and, importantly, an increase of M1 macrophages and a decrease of M2 macrophages inside the TME. Conclusions: Lefitolimod treatment resulted in modulation of the TME towards an increase of effector cells with anti-tumoral functions like cytotoxic CD8+ T cells and M1-type macrophages as well as a decrease of pro-tumoral M2-type macrophages. Therefore, lefitolimod provides the essential requirements for clinical response to immunotherapeutic drugs like checkpoint inhibitors. This predestines lefitolimod as combination partner in immuno-oncological trials.

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Human Cytomegalovirus Particles Treated with Specific Antibodies Induce Intrinsic and Adaptive but Not Innate Immune Responses

Journal of Virology ◽

10.1128/jvi.00678-17 ◽

2017 ◽

Vol 91 (22) ◽

Cited By ~ 2

Author(s):

Zeguang Wu ◽

Ruifang Qin ◽

Li Wang ◽

Matteo Bosso ◽

Myriam Scherer ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Human Cytomegalovirus ◽

Hcmv Infection ◽

Current Knowledge ◽

Passive Immunization ◽

Clinical Results ◽

Effector Cells ◽

Immunoglobulin Preparations

ABSTRACT Human cytomegalovirus (HCMV) persistently infects 40% to 100% of the human population worldwide. Experimental and clinical evidence indicates that humoral immunity to HCMV plays an important role in restricting virus dissemination and protecting the infected host from disease. Specific immunoglobulin preparations from pooled plasma of adults selected for high titers of HCMV antibodies have been used for the prevention of CMV disease in transplant recipients and pregnant women. Even though incubation of HCMV particles with these preparations leads to the neutralization of viral infectivity, it is still unclear whether the antibody-treated HCMV particles (referred to here as HCMV-Ab) enter the cells and modulate antiviral immune responses. Here we demonstrate that HCMV-Ab did enter macrophages. HCMV-Ab did not initiate the expression of immediate early antigens (IEAs) in macrophages, but they induced an antiviral state and rendered the cells less susceptible to HCMV infection upon challenge. Resistance to HCMV infection seemed to be due to the activation of intrinsic restriction factors and was independent of interferons. In contrast to actively infected cells, autologous NK cells did not degranulate against HCMV-Ab-treated macrophages, suggesting that these cells may not be eliminated by innate effector cells. Interestingly, HCMV-Ab-treated macrophages stimulated the proliferation of autologous adaptive CD4+ and CD8+ T cells. Our findings not only expand the current knowledge on virus-antibody immunity but may also be relevant for future vaccination strategies. IMPORTANCE Human cytomegalovirus (HCMV), a common herpesvirus, establishes benign but persistent infections in immunocompetent hosts. However, in subjects with an immature or dysfunctional immune system, HCMV is a major cause of morbidity and mortality. Passive immunization has been used in different clinical settings with variable clinical results. Intravenous hyperimmune globulin preparations (IVIg) are obtained from pooled adult human plasma selected for high anti-CMV antibody titers. While HCMV neutralization can be shown in vitro using different systems, data are lacking regarding the cross-influence of IVIg administration on the cellular immune responses. The aim of this study was to evaluate the effects of IVIg on distinct components of the immune response against HCMV, including antigen presentation by macrophages, degranulation of innate natural killer cells, and proliferation of adaptive CD4+ and CD8+ T cells.

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