TY - JOUR

T1 - Common phenotypic dynamics of tumor-infiltrating lymphocytes across different histologies upon checkpoint inhibition

T2 - impact on clinical outcome

AU - Araujo B de Lima, Vinicius

AU - Borch, Annie

AU - Hansen, Morten

AU - Draghi, Arianna

AU - Spanggaard, Iben

AU - Rohrberg, Kristoffer

AU - Reker Hadrup, Sine

AU - Lassen, Ulrik

AU - Svane, Inge Marie

N1 - Copyright © 2020 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.

PY - 2020/4

Y1 - 2020/4

N2 - BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapeutic landscape and our perception of interactions between the immune system and tumor cells. Despite remarkable progress, disease relapse and primary resistance are not uncommon. Understanding the biological processes that tumor-infiltrating lymphocytes (TILs) undergo during ICI, how this affects the tumor microenvironment (TME) and, ultimately, clinical outcome is, therefore, necessary to further improve treatment efficacy.AIM: In the current study, we sought to characterize TILs from patients with metastatic solid tumors undergoing ICI correlating flowcytometric findings with clinical outcome.METHODS: In total, 20 patients with 10 different metastatic solid tumors treated with ICIs targeting programmed-cell death-1 (PD-1)/PD-L1 axis were included in this study. The phenotype of T cells deriving from biopsies obtained prior to treatment initiation and on-treatment was investigaded. Analyses were focused on T cells' degree of differentiation and activity and how they correlate with transcriptomic changes in the TME.RESULTS: Data indicate that patients benefitting from ICIs accumulate CD8+central memory T cells. TILs developed an effector-like phenotype over time, which was also associated with a cytolytic gene signature. In terms of modulation of T-cell responses, we observed that high expression of checkpoint molecules pre-treatment (i.e., PD-1, lymphocyte activation gene-3 [LAG-3], B and T-lymphocyte attenuator [BTLA] and T-cell immunoglobulin and mucin domain containing-3 [TIM-3]) was associated with similar gene signature and correlated to treatment benefit. Increasing expression of LAG-3 and BTLA in the CD8 compartment and their co-expression with PD-1 during treatment were, however, a common feature for patients who failed to respond to ICIs.CONCLUSIONS: Besides identifying immune profiles suggestive of response to ICI, our results provide a more nuanced picture regarding expression of checkpoint molecules that goes beyond T-cell anergy.

AB - BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapeutic landscape and our perception of interactions between the immune system and tumor cells. Despite remarkable progress, disease relapse and primary resistance are not uncommon. Understanding the biological processes that tumor-infiltrating lymphocytes (TILs) undergo during ICI, how this affects the tumor microenvironment (TME) and, ultimately, clinical outcome is, therefore, necessary to further improve treatment efficacy.AIM: In the current study, we sought to characterize TILs from patients with metastatic solid tumors undergoing ICI correlating flowcytometric findings with clinical outcome.METHODS: In total, 20 patients with 10 different metastatic solid tumors treated with ICIs targeting programmed-cell death-1 (PD-1)/PD-L1 axis were included in this study. The phenotype of T cells deriving from biopsies obtained prior to treatment initiation and on-treatment was investigaded. Analyses were focused on T cells' degree of differentiation and activity and how they correlate with transcriptomic changes in the TME.RESULTS: Data indicate that patients benefitting from ICIs accumulate CD8+central memory T cells. TILs developed an effector-like phenotype over time, which was also associated with a cytolytic gene signature. In terms of modulation of T-cell responses, we observed that high expression of checkpoint molecules pre-treatment (i.e., PD-1, lymphocyte activation gene-3 [LAG-3], B and T-lymphocyte attenuator [BTLA] and T-cell immunoglobulin and mucin domain containing-3 [TIM-3]) was associated with similar gene signature and correlated to treatment benefit. Increasing expression of LAG-3 and BTLA in the CD8 compartment and their co-expression with PD-1 during treatment were, however, a common feature for patients who failed to respond to ICIs.CONCLUSIONS: Besides identifying immune profiles suggestive of response to ICI, our results provide a more nuanced picture regarding expression of checkpoint molecules that goes beyond T-cell anergy.

KW - Adult

KW - Aged

KW - B7-H1 Antigen/antagonists & inhibitors

KW - Biopsy

KW - CD8-Positive T-Lymphocytes/immunology

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Immunologic Factors/pharmacology

KW - Immunotherapy/methods

KW - Lymphocytes, Tumor-Infiltrating/drug effects

KW - Male

KW - Middle Aged

KW - Molecular Targeted Therapy/methods

KW - Neoplasms/pathology

KW - Phenotype

KW - Programmed Cell Death 1 Receptor/antagonists & inhibitors

KW - Treatment Outcome

KW - Tumor Microenvironment/drug effects

U2 - 10.1016/j.jcyt.2020.01.010

DO - 10.1016/j.jcyt.2020.01.010

M3 - Journal article

C2 - 32201034

VL - 22

SP - 204

EP - 213

JO - Cytotherapy

JF - Cytotherapy

SN - 1465-3249

IS - 4

ER -