Authors:	Bartneck, Joschka Hartmann, Ann-Kathrin Stein, Lara Arnold-Schild, Danielle Klein, Matthias Stassen, Michael Marini, Federico Pielenhofer, Jonas Meiser, Sophie Luise Langguth, Peter Mack, Matthias Muth, Sabine Probst, Hans-Christian Schild, Hansjörg Radsak, Markus Philipp
Title:	Tumor-infiltrating CCR2+ inflammatory monocytes counteract specific immunotherapy
Online publication date:	19-Feb-2024
Year of first publication:	2023
Language:	english
Abstract:	Tumor development and progression is shaped by the tumor microenvironment (TME), a heterogeneous assembly of infiltrating and resident host cells, their secreted mediators and intercellular matrix. In this context, tumors are infiltrated by various immune cells with either pro-tumoral or anti-tumoral functions. Recently, we published our non-invasive immunization platform DIVA suitable as a therapeutic vaccination method, further optimized by repeated application (DIVA2). In our present work, we revealed the therapeutic effect of DIVA2 in an MC38 tumor model and specifically focused on the mechanisms induced in the TME after immunization. DIVA2 resulted in transient tumor control followed by an immune evasion phase within three weeks after the initial tumor inoculation. High-dimensional flow cytometry analysis and single-cell mRNA-sequencing of tumor-infiltrating leukocytes revealed cytotoxic CD8+ T cells as key players in the immune control phase. In the immune evasion phase, inflammatory CCR2+ PDL-1+ monocytes with immunosuppressive properties were recruited into the tumor leading to suppression of DIVA2-induced tumor-reactive T cells. Depletion of CCR2+ cells with specific antibodies resulted in prolonged survival revealing CCR2+ monocytes as important for tumor immune escape in the TME. In summary, the present work provides a platform for generating a strong antigen-specific primary and memory T cell immune response using the optimized transcutaneous immunization method DIVA2. This enables protection against tumors by therapeutic immune control of solid tumors and highlights the immunosuppressive influence of tumor infiltrating CCR2+ monocytes that need to be inactivated in addition for successful cancer immunotherapy.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-10047
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	Frontiers in immunology 14
Pages or article number:	1267866
Publisher:	Frontiers Media S.A.
Publisher place:	Switzerland
Issue date:	2023
ISSN:	1664-3224
Publisher DOI:	10.3389/fimmu.2023.1267866
Appears in collections:	DFG-491381577-G