Anti-PD-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes Lm- LLO immunotherapyReportar como inadecuado




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Journal for ImmunoTherapy of Cancer

, 1:15

Basic Tumor Immunology

Abstract

BackgroundOne of the significant tumor immune escape mechanisms and substantial barrier for successful immunotherapy is tumor-mediated inhibition of immune response through cell-to-cell or receptor-ligand interactions. Programmed death receptor-1 PD-1 interaction with its ligands, PD-L1 and PD-L2, is one of the important strategies that many tumors employ to escape immune surveillance. Upon PD-Ls binding to PD-1, T cell receptor TCR signaling is dampened, causing inhibition of proliferation, decreased cytokine production, anergy and-or apoptosis. Thus PD-Ls expression by tumor cells serves as a protective mechanism, leading to suppression of tumor-infiltrating lymphocytes in the tumor microenvironment. Lm-LLO immunotherapies have been shown to be therapeutically effective due to their ability to induce potent antigen-specific immune responses. However, it has been demonstrated that infection with Lm leads to up-regulation of PD-L1 on mouse immune cells that can inhibit effector T cells through PD-1-PD-L1 pathway.

MethodsTherapeutic and immune efficacy of Listeria-based vaccine Lm-LLO-E7 in combination with anti-PD-1 antibody was tested in E7 antigen expressing TC-1 mouse tumor model. Tumor growth, survival, as well as peripheral and tumor-infiltrating immune cell profiles after immunotherapy were assessed.

ResultsHere we demonstrate that the combination of an Lm-LLO immunotherapy with anti-PD-1 antibody that blocks PD-1-PD-L1 interaction, significantly improves immune and therapeutic efficacy of treatment in TC-1 mouse tumor model. Importantly, we show that in addition to significant reduction of regulatory T cells Treg and myeloid-derived suppressor cells MDSC in both spleen and tumor microenvironment that are mediated solely by the Lm-LLO immunotherapy, the addition of anti-PD-1 antibody to the treatment results in significant increase of antigen-specific immune responses in periphery and CD8 T cell infiltration into the tumor. As a result, this combinational treatment leads to significant inhibition of tumor growth and prolonged survival-complete regression of tumors in treated animals.

We also demonstrate that in vitro infection with Lm results in significant upregulation of surface PD-L1 expression on human monocyte-derived dendritic cells suggesting the translational capacity of this finding.

ConclusionsOur findings demonstrate that combination of Lm-LLO-based vaccine with blocking of PD-1-PD-L1 interaction is a feasible approach with clinical translation potential that can lead to overall enhancement of the efficacy of anti-tumor immunotherapy.

KeywordsPD-1 Immunotherapy Listeria-based vaccine Combinational immunotherapy AbbreviationsPD-1Programmed death receptor-1

PD-L1-2Programmed death receptor-1 ligand1-2

TCRT cell receptor

LmListeria monocytogene

LLOListeriolysin-O

TregRegulatory T cell, MDSC- myeloid-derived suppressor cells

PAMPPathogen-associated molecular pattern

HPV16Human papillomavirus strain 16

CFUColony-forming unit

DCDendritic cell

PBMCPeripheral blood mononuclear cells

PEPhycoerythrin

FITCFluorescein isothiocyanate

AbAntibody

CTLCytotoxic T lymphocyte

CPMCyclophosphamide.

Electronic supplementary materialThe online version of this article doi:10.1186-2051-1426-1-15 contains supplementary material, which is available to authorized users.

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Autor: Mikayel Mkrtichyan - Namju Chong - Rasha Abu Eid - Anu Wallecha - Reshma Singh - John Rothman - Samir N Khleif

Fuente: https://link.springer.com/



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