scholarly journals Annexin A1 as a Regulator of Immune Response in Cancer

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2245
Author(s):  
Thaise Gonçalves Araújo ◽  
Sara Teixeira Soares Mota ◽  
Helen Soares Valença Ferreira ◽  
Matheus Alves Ribeiro ◽  
Luiz Ricardo Goulart ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Annexin A1 ◽  
Autocrine Signaling ◽  
Regulatory T Lymphocytes ◽  
Anti Inflammatory ◽  
Tumor Growth And Metastasis

Annexin A1 is a 37 kDa phospholipid-binding protein that is expressed in many tissues and cell types, including leukocytes, lymphocytes and epithelial cells. Although Annexin A1 has been extensively studied for its anti-inflammatory activity, it has been shown that, in the cancer context, its activity switches from anti-inflammatory to pro-inflammatory. Remarkably, Annexin A1 shows pro-invasive and pro-tumoral properties in several cancers either by eliciting autocrine signaling in cancer cells or by inducing a favorable tumor microenvironment. Indeed, the signaling of the N-terminal peptide of AnxA1 has been described to promote the switching of macrophages to the pro-tumoral M2 phenotype. Moreover, AnxA1 has been described to prevent the induction of antigen-specific cytotoxic T cell response and to play an essential role in the induction of regulatory T lymphocytes. In this way, Annexin A1 inhibits the anti-tumor immunity and supports the formation of an immunosuppressed tumor microenvironment that promotes tumor growth and metastasis. For these reasons, in this review we aim to describe the role of Annexin A1 in the establishment of the tumor microenvironment, focusing on the immunosuppressive and immunomodulatory activities of Annexin A1 and on its interaction with the epidermal growth factor receptor.

scholarly journals Targeting of the Cancer-Associated Fibroblast—T-Cell Axis in Solid Malignancies

2019 ◽  
Vol 8 (11) ◽  
pp. 1989 ◽  
Author(s):  
Tom J. Harryvan ◽  
Els M. E. Verdegaal ◽  
James C. H. Hardwick ◽  
Lukas J. A. C. Hawinkels ◽  
Sjoerd H. van der Burg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Suppressor Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Cell Axis ◽  
Wide Range

The introduction of a wide range of immunotherapies in clinical practice has revolutionized the treatment of cancer in the last decade. The majority of these therapeutic modalities are centered on reinvigorating a tumor-reactive cytotoxic T-cell response. While impressive clinical successes are obtained, the majority of cancer patients still fail to show a clinical response, despite the fact that their tumors express antigens that can be recognized by the immune system. This is due to a series of other cellular actors, present in or attracted towards the tumor microenvironment, including regulatory T-cells, myeloid-derived suppressor cells and cancer-associated fibroblasts (CAFs). As the main cellular constituent of the tumor-associated stroma, CAFs form a heterogeneous group of cells which can drive cancer cell invasion but can also impair the migration and activation of T-cells through direct and indirect mechanisms. This singles CAFs out as an important next target for further optimization of T-cell based immunotherapies. Here, we review the recent literature on the role of CAFs in orchestrating T-cell activation and migration within the tumor microenvironment and discuss potential avenues for targeting the interactions between fibroblasts and T-cells.

scholarly journals The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

2021 ◽  
Vol 22 (17) ◽  
pp. 9550
Author(s):  
Camila Morais Melo ◽  
Thiago Vidotto ◽  
Luiz Paulo Chaves ◽  
William Lautert-Dutra ◽  
Rodolfo Borges dos Reis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Response ◽  
Tumor Microenvironment ◽  
Somatic Mutations ◽  
Checkpoint Inhibitors ◽  
Molecular Genetic ◽  
Cell Types ◽  
T Cell Response ◽  
Cancer Genes ◽  
Regulatory Pathways

Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.

Dynamics of the Cytotoxic T Cell Response to a Model of Acute Viral Infection

immuneACCESS ◽  
2018 ◽  
Author(s):  
WS DeWitt ◽  
RO Emerson ◽  
P Lindau ◽  
M Vignali ◽  
TM Snyder ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Infection ◽  
Cell Response ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Acute Viral Infection

Functional management of an antiviral cytotoxic T-cell response.

1997 ◽  
Vol 71 (8) ◽  
pp. 5764-5768 ◽  
Author(s):  
M F Bachmann ◽  
D E Speiser ◽  
P S Ohashi
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Functional Management

scholarly journals DRES-13. DUAL KINASE INHIBITION TO COMBAT EGFR-INHIBITOR RESISTANCE IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi74-vi74
Author(s):  
Erin Smithberger ◽  
Abigail Shelton ◽  
Madison Butler ◽  
Alex Flores ◽  
Ryan Bash ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Alternative Pathway ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Genetically Engineered ◽  
Differentially Expressed ◽  
Egfr Inhibitor ◽  
Tumor Resistance ◽  
Pten Deletion ◽  
In Cells

Abstract Glioblastoma (GBM) is an aggressive primary brain tumor with a poor survival rate. One of the most common molecular alterations seen in GBM is amplification and/or mutation of the Epidermal Growth Factor Receptor (EGFR), which has made it an attractive therapeutic target. However, several EGFR tyrosine kinase inhibitors have been tested clinically in GBM with minimal success. One reason for this lack of efficacy could be due to acute, adaptive resistance via alternative pathway activation. To investigate this mechanism of tumor resistance, we used RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the transcriptomes and kinomes of genetically engineered murine astrocytes with common GBM genotypes. We have previously shown that 38% of the expressed kinome varied among a panel of diverse nGEM astrocytes harboring Cdkn2a deletion (C) plus Pten deletion (CP), wild-type human EGFR (CE) or EGFRvIII (CEv3) overexpression or both EGFRvIII overexpression and Pten deletion (CEv3P). Although CE have a similar transcriptional profile to C cells at baseline, when treated with the EGFR inhibitor afatinib, CE respond more similarly to CEv3 cells. When cells containing endogenous murine EGFR (C and CP) are treated with afatinib, fewer than 0.5% of kinases showed differential expression. In cells with EGFR overexpression alone, more than 6% of kinases were differentially expressed upon afatinib treatment, including Ntrk3, Fgfr2 and 3, Lyn, Bmx, Epha2 and 5, Fn3k, a kinase involved in fructosamine processing, and Nrbp2, a kinase involved in regulation of apoptosis. This effect was blunted in cells lacking Pten in addition to having EGFRvIII (CEv3P), resulting in less than 2% of kinases being differentially expressed. The only kinase upregulated in all three EGFR-overexpressing cell types was Coq8a, which is involved in electron transport and response to DNA damage. Given this overlap in response, Coq8a could be a potential dual treatment target for GBM.

Augmented induction of CD8+ cytotoxic T-cell response and antitumor effect by DCs pulsed with virus-like particles packaging with CpG

2007 ◽  
Vol 256 (1) ◽  
pp. 90-100 ◽  
Author(s):  
Shuxia Song ◽  
Yue Wang ◽  
Yan Zhang ◽  
Fang Wang ◽  
Ying He ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Antitumor Effect ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Virus Like Particles

scholarly journals Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

2021 ◽  
Vol 10 (1) ◽  
pp. 1956143
Author(s):  
Anna Sosnowska ◽  
Justyna Chlebowska-Tuz ◽  
Pawel Matryba ◽  
Zofia Pilch ◽  
Alan Greig ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Lung Carcinoma ◽  
Cell Response ◽  
T Cell Response

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 TAMI-07. THE IMMUNE MICROENVIRONMENT IN LOWER GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Anupam Kumar ◽  
Katharine Chen ◽  
Claudia Petritsch ◽  
Theodore Nicolaides ◽  
Mariarita Santi-Vicini ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Lower Grade ◽  
Functional Relationships

Abstract The determinants of the tumor-associated immune response in brain tumors are poorly understood. Using tumor samples from two molecularly distinct subtypes of lower grade glioma, MAPK-driven glioma with biallelic inactivation of CDKN2A (n=30) and IDH-mutant, 1p/19q-intact astrocytoma (n=29), we demonstrate qualitative and quantitative differences in the tumor-associated immune response and we investigate the molecular mechanisms involved. Histologically the MAPK-driven gliomas were comprised of pleomorphic xanthoastrocytoma (PXA) (n=11) and anaplastic PXA (n=19). Seven patients had paired samples from two sequential surgeries. Immune cell populations and their activity were determined by quantitative multiplex immunostaining and Digital Spatial Profiling and gene expression was analyzed by Nanostring. Functional studies were performed using established cell lines and two new patient-derived lines from MAPK-driven LGGs. MAPK-driven tumors exhibited an increased number of CD8+ T cells and tumor-associated microglial/macrophage (TAMs), including CD163+ TAMs, as compared to IDH-mutant astrocytoma. In contrast, IDH-mutant tumors had increased FOXP3+ immunosuppressive T regulatory cells. Transcriptional and protein level analyses in MAPK-driven tumors suggested an active cytotoxic T cell response with robust expression of granzyme B, present on 27% of CD8+ T cells, increased MHC class I expression, and altered cytokine profiles. Interestingly, MAPK-driven tumors also had increased expression of immunosuppressive molecules, including CXCR4, PD-L1, and VEGFA. Expression differences for cell surface and secreted proteins were confirmed in patient-derived tumor lines and functional relationships between altered chemokine expression and immune cell infiltration was investigated. Our data provide novel insights into the immune contexture of MAPK driven LGGs and suggest MAPK driven gliomas with biallelic inactivation of CDKN2A may be particularly vulnerable to immunotherapeutic modulation

scholarly journals Lymphocytic Choriomeningitis Virus Alters the Expression of Male Mouse Scent Proteins

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1180
Author(s):  
Michael B. A. Oldstone ◽  
Brian C. Ware ◽  
Amanda Davidson ◽  
Mark C. Prescott ◽  
Robert J. Beynon ◽  
...  
Keyword(s):  
Mate Selection ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Response ◽  
Mature Male ◽  
Cytotoxic T Cell ◽  
Scent Marks ◽  
High Concentration ◽  
Embryo Survival ◽  
Major Urinary Proteins ◽  
The Individual

Mature male mice produce a particularly high concentration of major urinary proteins (MUPs) in their scent marks that provide identity and status information to conspecifics. Darcin (MUP20) is inherently attractive to females and, by inducing rapid associative learning, leads to specific attraction to the individual male’s odour and location. Other polymorphic central MUPs, produced at much higher abundance, bind volatile ligands that are slowly released from a male’s scent marks, forming the male’s individual odour that females learn. Here, we show that infection of C57BL/6 males with LCMV WE variants (v2.2 or v54) alters MUP expression according to a male’s infection status and ability to clear the virus. MUP output is substantially reduced during acute adult infection with LCMV WE v2.2 and when males are persistently infected with LCMV WE v2.2 or v54. Infection differentially alters expression of darcin and, particularly, suppresses expression of a male’s central MUP signature. However, following clearance of acute v2.2 infection through a robust virus-specific CD8 cytotoxic T cell response that leads to immunity to the virus, males regain their normal mature male MUP pattern and exhibit enhanced MUP output by 30 days post-infection relative to uninfected controls. We discuss the likely impact of these changes in male MUP signals on female attraction and mate selection. As LCMV infection during pregnancy can substantially reduce embryo survival and lead to lifelong infection in surviving offspring, we speculate that females use LCMV-induced changes in MUP expression both to avoid direct infection from a male and to select mates able to develop immunity to local variants that will be inherited by their offspring.

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