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Your search keyword '"TIL (tumor infiltrating lymphocytes)"' showing total 4 results
Start Over Descriptor "TIL (tumor infiltrating lymphocytes)" Topic immunotherapy
4 results on '"TIL (tumor infiltrating lymphocytes)"'

1. Strategies to Overcome Failures in T-Cell Immunotherapies by Targeting PI3K-δ and -γ.

Author

Chandrasekaran S, Funk CR, Kleber T, Paulos CM, Shanmugam M, and Waller EK

Subjects
Animals, Biomarkers, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Class I Phosphatidylinositol 3-Kinases metabolism, Class Ib Phosphatidylinositol 3-Kinase metabolism, Disease Management, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Immunotherapy, Adoptive, Lymphocyte Activation immunology, Molecular Targeted Therapy, Signal Transduction, Translational Research, Biomedical, Class I Phosphatidylinositol 3-Kinases immunology, Class Ib Phosphatidylinositol 3-Kinase immunology, Immunotherapy methods, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
Abstract

PI3K-δ and PI3K-γ are critical regulators of T-cell differentiation, senescence, and metabolism. PI3K-δ and PI3K-γ signaling can contribute to T-cell inhibition via intrinsic mechanisms and regulation of suppressor cell populations, including regulatory T-cells and myeloid derived suppressor cells in the tumor. We examine an exciting new role for using selective inhibitors of the PI3K δ- and γ-isoforms as modulators of T-cell phenotype and function in immunotherapy. Herein we review the current literature on the implications of PI3K-δ and -γ inhibition in T-cell biology, discuss existing challenges in adoptive T-cell therapies and checkpoint blockade inhibitors, and highlight ongoing efforts and future directions to incorporate PI3K-δ and PI3K-γ as synergistic T-cell modulators in immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chandrasekaran, Funk, Kleber, Paulos, Shanmugam and Waller.)

Published
2021
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2. Triple negative breast cancer: Immunogenicity, tumor microenvironment, and immunotherapy

Author

Sotiris Loizides and Anastasia Constantinidou

Subjects
immunotherapy, triple negative breast cancer, TIL (tumor infiltrating lymphocytes), tumor microenvironment, PD-L1 expression, Genetics, QH426-470
Abstract

Triple negative breast cancer (TNBC) is a biologically diverse subtype of breast cancer characterized by genomic and transcriptional heterogeneity and exhibiting aggressive clinical behaviour and poor prognosis. In recent years, emphasis has been placed on the identification of mechanisms underlying the complex genomic and biological profile of TNBC, aiming to tailor treatment strategies. High immunogenicity, specific immune activation signatures, higher expression of immunosuppressive genes and higher levels of stromal Tumor Infiltrating Lymphocytes, constitute some of the key elements of the immune driven landscape associated with TNBC. The unprecedented response of TNBC to immunotherapy has undoubtedly changed the standard of care in this disease both in the early and the metastatic setting. However, the extent of interplay between immune infiltration and mutational signatures in TNBC is yet to be fully unravelled. In the present review, we present clinical evidence on the immunogenicity and tumour microenvironment influence on TNBC progression and the current treatment paradigms in TNBC based on immunotherapy.

Published
2023
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3. Transcriptome Analysis of Tumor-Infiltrating Lymphocytes Identifies NK Cell Gene Signatures Associated With Lymphocyte Infiltration and Survival in Soft Tissue Sarcomas.

Author

Judge, Sean J., Bloomstein, Joshua D., Sholevar, Cyrus J., Darrow, Morgan A., Stoffel, Kevin M., Vick, Logan V., Dunai, Cordelia, Cruz, Sylvia M., Razmara, Aryana M., Monjazeb, Arta M., Rebhun, Robert B., Murphy, William J., and Canter, Robert J.

Subjects
KILLER cells, TUMOR-infiltrating immune cells, SARCOMA, IMMUNOTHERAPY, TISSUE viability, LYMPHOCYTES
Abstract

Purpose: Clinical successes using current T-cell based immunotherapies have been limited in soft tissue sarcomas (STS), while pre-clinical studies have shown evidence of natural killer (NK) cell activity. Since tumor immune infiltration, especially tumor-infiltrating lymphocytes, is associated with improved survival in most solid tumors, we sought to evaluate the gene expression profile of tumor and blood NK and T cells, as well as tumor cells, with the goal of identifying potential novel immune targets in STS. Experimental Design: Using fluorescence-activated cell sorting, we isolated blood and tumor-infiltrating CD3-CD56+ NK and CD3+ T cells and CD45-viable tumor cells from STS patients undergoing surgery. We then evaluated differential gene expression (DGE) of these purified populations with RNA sequencing analysis. To evaluate survival differences and validate primary DGE results, we also queried The Cancer Genome Atlas (TCGA) database to compare outcomes stratified by bulk gene expression. Results: Sorted intra-tumoral CD3+ T cells showed significant upregulation of established activating (CD137) and inhibitory genes (TIM-3) compared to circulating T cells. In contrast, intra-tumoral NK cells did not exhibit upregulation of canonical cytotoxic genes (IFNG, GZMB), but rather significant DGE in mitogen signaling (DUSP4) and metabolic function (SMPD3, SLC7A5). Tumors with higher NK and T cell infiltration exhibited significantly increased expression of the pro-inflammatory receptor TLR4 in sorted CD45-tumor cells. TCGA analysis revealed that tumors with high TLR4 expression (P = 0.03) and low expression of STMN1 involved in microtubule polymerization (P < 0.001) were associated with significantly improved survival. Conclusions: Unlike T cells, which demonstrate significant DGE consistent with upregulation of both activating and inhibiting receptors in tumor-infiltrating subsets, NK cells appear to have more stable gene expression between blood and tumor subsets, with alterations restricted primarily to metabolic pathways. Increased immune cell infiltration and improved survival were positively correlated with TLR4 expression and inversely correlated with STMN1 expression within tumors, suggesting possible novel therapeutic targets for immunotherapy in STS. [ABSTRACT FROM AUTHOR]

Published
2022
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4. Mise au point d'une technique d'immunohistochimie multiplex quantitative pour l'analyse du microenvironnement immunitaire tumoral

Author

Cochin, Sandrine, Reymann, Carine, Kehrer, Nadine, and Barraud, Luc

Subjects
Tumor immunophenotyping, OPAL, quantitative multiplex IF, immunotherapy, TIL (Tumor infiltrating Lymphocytes), immunophénotypage tumoral, IHC multiplex quantitative, immunothérapie, TIL (tumor infiltrating lymphocyte)
Abstract

Le contexte immunitaire influence la progression tumorale et le devenir des patients sous thérapies antitumorales. Plus précisément, le microenvironnement tumoral (TME) influence la progression des tumeurs et est désormais la cible des nouvelles immunothérapies. L’étude de cet environnement est désormais indispensable pour accompagner les traitements des patients. L’objectif de cette étude est de développer et d’évaluer des panels d’immunohistochimie (IHC) multiplex pour analyser le TME. L’IHC multiplex peut permettre d’analyser la complexité du TME et d’étudier directement in situ les interactions entre les nombreuses populations cellulaires qui le composent. Dans cette étude préliminaire, nous avons développé un panel pour l’analyse des lymphocytes infiltrants la tumeur (TIL), et réalisé une évaluation de la méthode d’analyse des images. La méthode utilisée est une IHC multiplex révélée en immunofluorescence (IF) avec le système d’amplification du signal à la tyramide (TSA) développé par Perkin Elmer sous le nom de système Opal suite à un partenariat. Cette technologie a été notamment adaptée sur l’automate Leica BOND RXm utilisé pour cette étude. Pour l’analyse des TIL, nous avons développé un panel CD4, CD8 et CD20 permettant de cibler respectivement les lymphocytes T helper, T cytotoxiques et B. Après l’IF multiplex et le scan des lames, les marqueurs ont été quantifiés par analyse d’image en utilisant le logiciel CaloPix de Tribvn. La méthode d’analyse a été évaluée en étudiant la justesse des résultats quantitatifs obtenus en multiplex par rapport aux analyses simples et la reproductibilité du process, réalisé par plusieurs opérateurs. Ces analyses ont été faites sur plusieurs types tumoraux : cancer du poumon (NSCLC), du sein (BC) du pancréas (PC), du cerveau, un glioblastome (G) et un cancer du foie (HCC). La variabilité induite par la nature de l’échantillon a également été adressée. Résultats : Nous avons observé que la justesse de l’analyse multiplex est impactée par le type tumoral étudié. Une bonne correspondance entre les simplex et le multiplex est observée pour les BC, PC et NSCL, mais est plus difficile à obtenir pour le Glioblastome et le HCC. La reproductibilité est également impactée par la nature du tissu. Ces premiers résultats montrent que la standardisation de la méthode d’analyse reste à parfaire pour diminuer ces variations. 163 Revue Française d’Histotechnologie 2018 - Vol. 30 - n°1 En conclusion, le développement de nouveaux biomarqueurs in situ est fondamental pour comprendre le fonctionnement du microenvironnement tumoral et des nouveaux produits d’immunothérapie. Nous décrivons ici un exemple de développement d’IHC multiplex quantitative, outil qui sera essentiel pour analyser le système immunitaire in situ et pour accompagner les traitements des patients. Nous soulignons également que les méthodes d’analyses de ces IHC nécessiteront des process de validations à ne pas négliger avant une utilisation automatisée., Immune background influences cancer progression and clinical outcome of patients. The tumor microenvironment (TME) is the bed of cancer progression and the target of developing drugs. The objective of this work is to develop and evaluate multiplex ImmunoHistoChemical (IHC) panels to analyze the immuno-phenotype of human cancer TME. Multiplex IHC can be used to analyze the complexity of TME and to study directly in situ the interactions between the many cellular populations that compose it. We describe here the preliminary work on the analysis of the Tumor Infiltrating Lymphocyte (TIL), and the evaluation of the process we performed on image analysis. Methods of labelling are based on a Tyramide Signal Amplification (TSA) fluorescence (IF) coupled developed by PerkinElmer (Opal® technology) and realized on Leica BOND RXm system. For TIL analysis, we developed a panel composed of CD4, CD8 and CD20 markers allowing to respectively detect T helper, T cytotoxic and B lymphocytes. After multiplex OPAL labelling and slide scanning, quantifications of all markers were performed using CaloPix software from Tribvn. These analyses were performed on human tumors: Non-Small Cell Lung Carcinoma (NSCLC), Breast carcinoma (BC), Pancreatic carcinoma (PC), Glioblastoma (G) and Hepatocellular Carcinoma (HCC). Results: We observed that accuracy of the image analysis method 164 Revue Française d’Histotechnologie 2018 - Vol. 30 - n°1 for TIL quantification was variable depending of the tumor. We observed globally a good concordance between simplex and multiplex quantification in BC, PC and NSCLC. This concordance was more difficult to obtain with G and HCC and further improvements need in the formalization of the analysis process. In conclusion, the development of new in situ biomarkers is fundamental to understand the influence of TME on tumor progression for immunotherapeutic development. We describe here the development of multiplex IHC panel for TIL analysis that will allow the immune “phenotyping” of this TME. We highlight also that the analysis process of theses multiplex IHC will need to be correctly validated before use in an automatic way.

Published
2018
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