scholarly journals Immune checkpoint proteins CTLA-4, PD-1 and PD-L1 in melanoma as predictive biomarkers to guide clinical decisions

2020 ◽  
Author(s):  
Markus Tiemann ◽  
Vera Samoilova ◽  
Dmitri Atiakshin ◽  
Igor Buchwalow
Keyword(s):  
Tumor Microenvironment ◽  
T Lymphocytes ◽  
Predictive Biomarkers ◽  
Cell Types ◽  
Clinical Decisions ◽  
Diagnostic Significance ◽  
Lymphocyte Activity ◽  
Immune Checkpoint Proteins ◽  
Antigen Presenting ◽  
In Cells

Abstract Background CTLA-4, PD-1 and PD-L1 are potential targets in cancer immunotherapy. However, to predict patients who are likely to respond to treatment with PD-1/PD-L1/CTLA-4 blockers still remains a challenge. Unfortunately, it is often ignored that CTLA-4 exists also in cells other than lymphocytes. This study aimed to assess the expression and diagnostic significance of predictive biomarkers for melanoma. Methods To address this issue, we performed an immunophenotyping of CTLA4/PD1/PD-L1-positive cells in melanoma employing multiple immunofluorescent immunolabeling. For immunolabeling, we used primary antibodies to PD-1 and PD-L1, a panel of anti–CTLA-4 antibodies of different clones and a panel of CD antibodies against diverse cell types (CD1a, CD3, CD8 and CD68). Results In contrast to the currently accepted view, immunolabeling with anti-CTLA-4 antibodies of different clones permitted to reveal CTLA-4 in cells other than lymphocytes. CTLA-4 and PD-L1 are both expressed in the tumor microenvironment cells including antigen-presenting cells ÷ macrophages and dendritic cells. PD-1 is expressed solely in T-lymphocytes. CTLA-4 and PD-L1 in melanoma are not expressed in malignant cells. Conclusion Accordingly, PD-L1 expression by tumor cells cannot serve as a biomarker of clinical response to checkpoint blockade in melanoma immunotherapy, but PD-L1 and CTLA-4 expressed in the tumor microenvironment cells are valuable biomarkers to guide clinical decisions. The expression of CTLA-4 also in cells other than T-lymphocytes suggests the involvement of this molecule in alternative CTLA-4 signaling pathways together with the well-known classical scheme for the regulation of T-lymphocyte activity.

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 Tumor microenvironment subtypes and immune-related signatures for the prognosis of breast cancer

2020 ◽  
Author(s):  
Yiqun Han ◽  
Jiayu Wang ◽  
Binghe Xu
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
T Lymphocytes ◽  
Cancer Patients ◽  
Prognostic Model ◽  
Cox Regression ◽  
Cell Types ◽  
Well Performance ◽  
Breast Cancer Patients ◽  
Cox Regression Analysis

Abstract To better understand the heterogeneity of tumor microenvironment (TME) and establish a prognostic model for breast cancer in clinical practice, the leukocyte infiltrations of 22 cell types of interest from 2620 breast cancer patients were quantitatively estimated using deconvolution algorithms, and three TME subtypes with distinct molecular and clinical features were identified by unsupervised clustering approach. Then, we carried out systematic analyses to illustrate the contributing mechanisms for differential phenotypes, which suggested that the divergences were distinguished by cell cycle dysfunction, variation of cytotoxic T lymphocytes activity. Next, through dimensionally reduction and selection based on random-forest analysis, least absolute shrinkage and selection operator (LASSO) analysis, and uni- and multivariate COX regression analysis, a total of 15 significant genes were proposed to construct the prognostic immune-related score (pIRS) system and, in combinations with clinicopathological characteristics, a predictive model was ultimately built with well performance for survival of breast cancer patients. Comparative analyses demonstrated that proactivity of CD8 T lymphocytes and hyper-angiogenesis could be attributed to distinct prognostic outcomes. In conclusion, we retrieved three TME phenotypes and the curated prognostic model based on pIRS system for breast cancer. This model is justified for validation and optimized in the coming future.

scholarly journals TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting

2019 ◽  
Vol 69 (2) ◽  
pp. 237-244 ◽  
Author(s):  
Marlies J. W. Peeters ◽  
Anne Rahbech ◽  
Per thor Straten
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Protein S ◽  
Cell Types ◽  
Therapy Resistance ◽  
Activated T Cells ◽  
Tam Receptors ◽  
Antigen Presenting ◽  
Different Cell Types

Abstract The TAM receptors—TYRO3, AXL, MERTK—are pleiotropically expressed receptors in both healthy and diseased tissue. A complex of the ligands Protein S (PROS1) or Growth Arrest-Specific 6 (GAS6) with apoptotic phosphatidylserine activates the TAM receptors. Hence, this receptor family is essential for the efferocytosis of apoptotic material by antigen-presenting cells. In addition, TAM receptors are expressed by virtually all cells of the tumor microenvironment. They are also potent oncogenes, frequently overexpressed in cancer and involved in survival and therapy resistance. Due to their pro-oncogenic and immune-inhibitory traits, TAM receptors have emerged as promising targets for cancer therapy. Recently, TAM receptors have been described to function as costimulatory molecules on human T cells. TAM receptors’ ambivalent functions on many different cell types therefore make therapeutic targeting not straight-forward. In this review we summarize our current knowledge of the function of TAM receptors in the tumor microenvironment. We place particular focus on TAM receptors and the recently unraveled role of MERTK in activated T cells and potential consequences for anti-tumor immunity.

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.

scholarly journals Human-interpretable image features derived from densely mapped cancer pathology slides predict diverse molecular phenotypes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
James A. Diao ◽  
Jason K. Wang ◽  
Wan Fung Chui ◽  
Victoria Mountain ◽  
Sai Chowdary Gullapally ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Image Features ◽  
Tissue Type ◽  
Type Model ◽  
Biologically Relevant ◽  
Cancer Pathology ◽  
Substantial Progress ◽  
Cancer Types ◽  
Molecular Phenotypes ◽  
Immune Checkpoint Proteins

AbstractComputational methods have made substantial progress in improving the accuracy and throughput of pathology workflows for diagnostic, prognostic, and genomic prediction. Still, lack of interpretability remains a significant barrier to clinical integration. We present an approach for predicting clinically-relevant molecular phenotypes from whole-slide histopathology images using human-interpretable image features (HIFs). Our method leverages >1.6 million annotations from board-certified pathologists across >5700 samples to train deep learning models for cell and tissue classification that can exhaustively map whole-slide images at two and four micron-resolution. Cell- and tissue-type model outputs are combined into 607 HIFs that quantify specific and biologically-relevant characteristics across five cancer types. We demonstrate that these HIFs correlate with well-known markers of the tumor microenvironment and can predict diverse molecular signatures (AUROC 0.601–0.864), including expression of four immune checkpoint proteins and homologous recombination deficiency, with performance comparable to ‘black-box’ methods. Our HIF-based approach provides a comprehensive, quantitative, and interpretable window into the composition and spatial architecture of the tumor microenvironment.

scholarly journals Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1374
Author(s):  
Claudia Corrò ◽  
Valérie Dutoit ◽  
Thibaud Koessler
Keyword(s):  
Rectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Infiltration ◽  
Emerging Trends ◽  
Tumor Mutational Burden ◽  
Microsatellite Stability

Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

scholarly journals Macrophage-dependent Apoptosis of CD4+ T Lymphocytes from HIV-infected Individuals Is Mediated by FasL and Tumor Necrosis Factor

1997 ◽  
Vol 185 (1) ◽  
pp. 55-64 ◽  
Author(s):  
Andrew D. Badley ◽  
David Dockrell ◽  
Margaret Simpson ◽  
Ron Schut ◽  
David H. Lynch ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Tumor Necrosis ◽  
Human Macrophages ◽  
Infected Cells ◽  
Induced Apoptosis ◽  
Antigen Presenting ◽  
Necrosis Factor

Apoptosis of bystander uninfected CD4+ T lymphocytes by neighboring HIV-infected cells is observed in cell culture and in lymphoid tissue of HIV-infected individuals. This study addresses whether antigen-presenting cells such as human macrophages mediate apoptosis of CD4+ T cells from HIV-infected individuals. Uninfected human macrophages, and to a larger degree, HIV-infected macrophages mediate apoptosis of T cells from HIV-infected, but not from uninfected control individuals. This macrophage-dependent killing targets CD4+, but not CD8+ T lymphocytes from HIV-infected individuals, and direct contact between macrophages and lymphocytes is required. Additional analyses indicated that the apoptosis-inducing ligands, FasL and tumor necrosis factor (TNF), mediate this macrophage-induced apoptosis of CD4+ T cells. These results support a role for macrophage-associated FasL and TNF in the selective depletion of CD4+ T cells in HIV-infected individuals.

scholarly journals Differential Regulation of Cathepsin S and Cathepsin L in Interferon γ–treated Macrophages

2003 ◽  
Vol 197 (2) ◽  
pp. 169-179 ◽  
Author(s):  
Courtney Beers ◽  
Karen Honey ◽  
Susan Fink ◽  
Katherine Forbush ◽  
Alexander Rudensky
Keyword(s):  
Cathepsin L ◽  
Specific Inhibitor ◽  
Cell Types ◽  
Interferon Γ ◽  
Cathepsin S ◽  
Antigen Presenting Cell ◽  
Relative Contribution ◽  
Helper Cell Type ◽  
Ifn Γ ◽  
Antigen Presenting

Cathepsin S (catS) and cathepsin L (catL) mediate late stages of invariant chain (Ii) degradation in discrete antigen-presenting cell types. Macrophages (Mϕs) are unique in that they express both proteases and here we sought to determine the relative contribution of each enzyme. We observe that catL plays no significant role in Ii cleavage in interferon (IFN)-γ–stimulated Mϕs. In addition, our studies show that the level of catL activity is significantly decreased in Mϕs cultured in the presence of IFN-γ whereas catS activity increases. The decrease in catL activity upon cytokine treatment occurs despite the persistence of high levels of mature catL protein, suggesting that a specific inhibitor of the enzyme is up-regulated in IFN-γ–stimulated peritoneal Mϕs. Similar inhibition of activity is observed in dendritic cells engineered to overexpress catL. Such enzymatic inhibition in Mϕs exhibits only partial dependence upon Ii and therefore, other mechanisms of catL inhibition are regulated by IFN-γ. Thus, during a T helper cell type 1 immune response catL inhibition in Mϕs results in preferential usage of catS, such that major histocompatibility complex class II presentation by all bone marrow–derived antigen-presenting cell is regulated by catS.

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