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In vitro 4-1BB stimulation promotes expansion of CD8+ tumor-infiltrating lymphocytes from various sarcoma subtypes

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@article{7b561ac080974321bfa1ad57b9bdea64,
title = "In vitro 4-1BB stimulation promotes expansion of CD8+ tumor-infiltrating lymphocytes from various sarcoma subtypes",
abstract = "Tumor-specific tumor-infiltrating lymphocytes (TILs) can be in vitro expanded and have the ability to induce complete and durable tumor regression in some patients with melanoma following adoptive cell therapy (ACT). In this preclinical study, we investigated the feasibility of expanding TIL from sarcomas, as well as performing functional in vitro analyses on these. TILs were expanded in vitro by the use of IL2 stimulation with or without the addition of 4-1BB and CD3 antibodies. Phenotypical and functional analyses were mainly performed by flow cytometry. TILs were expanded from 25 of 28 (89%) tumor samples from patients with 9 different sarcoma subtypes. TILs were predominantly αβ T-cells of effector memory subtype with CD4+  dominance. In particular, CD8+ TIL highly expressed LAG3 and to a lesser degree PD-1 and BTLA. In total, 10 of 20 TIL cultures demonstrated in vitro recognition of autologous tumor. In some cases, the fraction of tumor-reactive T cells was more than 20%. 4-1BB stimulation augmented expansion kinetics and favored CD8+ occurrence. In conclusion, TIL expansion from sarcoma is feasible and expanded TILs highly express LAG3 and comprise multifunctional tumor-reactive T-cells.",
keywords = "4-1BB Ligand/pharmacology, Adult, Aged, Aged, 80 and over, CD8-Positive T-Lymphocytes/drug effects, Cell Culture Techniques/methods, Female, Humans, Lymphocytes, Tumor-Infiltrating/drug effects, Male, Middle Aged, Sarcoma/immunology, Tumor Cells, Cultured",
author = "Morten Nielsen and Anders Krarup-Hansen and Dorrit Hovgaard and Petersen, {Michael M{\o}rk} and Loya, {Anand Chainsukh} and Westergaard, {Marie Christine Wulff} and Svane, {Inge Marie} and Niels Junker",
year = "2020",
month = nov,
doi = "10.1007/s00262-020-02568-x",
language = "English",
volume = "69",
pages = "2179--2191",
journal = "Cancer Immunology and Immunotherapy",
issn = "0340-7004",
publisher = "Springer",
number = "11",

}

RIS

TY - JOUR

T1 - In vitro 4-1BB stimulation promotes expansion of CD8+ tumor-infiltrating lymphocytes from various sarcoma subtypes

AU - Nielsen, Morten

AU - Krarup-Hansen, Anders

AU - Hovgaard, Dorrit

AU - Petersen, Michael Mørk

AU - Loya, Anand Chainsukh

AU - Westergaard, Marie Christine Wulff

AU - Svane, Inge Marie

AU - Junker, Niels

PY - 2020/11

Y1 - 2020/11

N2 - Tumor-specific tumor-infiltrating lymphocytes (TILs) can be in vitro expanded and have the ability to induce complete and durable tumor regression in some patients with melanoma following adoptive cell therapy (ACT). In this preclinical study, we investigated the feasibility of expanding TIL from sarcomas, as well as performing functional in vitro analyses on these. TILs were expanded in vitro by the use of IL2 stimulation with or without the addition of 4-1BB and CD3 antibodies. Phenotypical and functional analyses were mainly performed by flow cytometry. TILs were expanded from 25 of 28 (89%) tumor samples from patients with 9 different sarcoma subtypes. TILs were predominantly αβ T-cells of effector memory subtype with CD4+  dominance. In particular, CD8+ TIL highly expressed LAG3 and to a lesser degree PD-1 and BTLA. In total, 10 of 20 TIL cultures demonstrated in vitro recognition of autologous tumor. In some cases, the fraction of tumor-reactive T cells was more than 20%. 4-1BB stimulation augmented expansion kinetics and favored CD8+ occurrence. In conclusion, TIL expansion from sarcoma is feasible and expanded TILs highly express LAG3 and comprise multifunctional tumor-reactive T-cells.

AB - Tumor-specific tumor-infiltrating lymphocytes (TILs) can be in vitro expanded and have the ability to induce complete and durable tumor regression in some patients with melanoma following adoptive cell therapy (ACT). In this preclinical study, we investigated the feasibility of expanding TIL from sarcomas, as well as performing functional in vitro analyses on these. TILs were expanded in vitro by the use of IL2 stimulation with or without the addition of 4-1BB and CD3 antibodies. Phenotypical and functional analyses were mainly performed by flow cytometry. TILs were expanded from 25 of 28 (89%) tumor samples from patients with 9 different sarcoma subtypes. TILs were predominantly αβ T-cells of effector memory subtype with CD4+  dominance. In particular, CD8+ TIL highly expressed LAG3 and to a lesser degree PD-1 and BTLA. In total, 10 of 20 TIL cultures demonstrated in vitro recognition of autologous tumor. In some cases, the fraction of tumor-reactive T cells was more than 20%. 4-1BB stimulation augmented expansion kinetics and favored CD8+ occurrence. In conclusion, TIL expansion from sarcoma is feasible and expanded TILs highly express LAG3 and comprise multifunctional tumor-reactive T-cells.

KW - 4-1BB Ligand/pharmacology

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - CD8-Positive T-Lymphocytes/drug effects

KW - Cell Culture Techniques/methods

KW - Female

KW - Humans

KW - Lymphocytes, Tumor-Infiltrating/drug effects

KW - Male

KW - Middle Aged

KW - Sarcoma/immunology

KW - Tumor Cells, Cultured

U2 - 10.1007/s00262-020-02568-x

DO - 10.1007/s00262-020-02568-x

M3 - Journal article

C2 - 32472369

VL - 69

SP - 2179

EP - 2191

JO - Cancer Immunology and Immunotherapy

JF - Cancer Immunology and Immunotherapy

SN - 0340-7004

IS - 11

ER -

ID: 61244280