TNF-α-secreting tumor-infiltrated monocytes play a pivotal role during anti-PD-L1 immunotherapy
Fecha
2022Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Impacto
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10.3389/fimmu.2022.811867
Resumen
Immune checkpoint blockade (ICB) of the PD-1 pathway revolutionized the survival forecast for advanced non-small cell lung cancer (NSCLC). Yet, the majority of PD-L1+ NSCLC patients are refractory to anti-PD-L1 therapy. Recent observations indicate a pivotal role for the PD-L1+ tumor-infiltrating myeloid cells in therapy failure. As the latter comprise a heterogenous population in the lung tumor ...
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Immune checkpoint blockade (ICB) of the PD-1 pathway revolutionized the survival forecast for advanced non-small cell lung cancer (NSCLC). Yet, the majority of PD-L1+ NSCLC patients are refractory to anti-PD-L1 therapy. Recent observations indicate a pivotal role for the PD-L1+ tumor-infiltrating myeloid cells in therapy failure. As the latter comprise a heterogenous population in the lung tumor microenvironment, we applied an orthotopic Lewis Lung Carcinoma (LLC) model to evaluate 11 different tumor-residing myeloid subsets in response to anti-PD-L1 therapy. While we observed significantly reduced fractions of tumor-infiltrating MHC-IIlow macrophages and monocytes, serological levels of TNF-a restored in lung tumor-bearing mice. Notably, we demonstrated in vivo and in vitro that anti-PD-L1 therapy mediated a monocytespecific production of, and response to TNF-a, further accompanied by their significant upregulation of CD80, VISTA, LAG-3, SIRP-a and TIM-3. Nevertheless, co-blockade of PD-L1 and TNF-a did not reduce LLC tumor growth. A phenomenon that was partly explained by the observation that monocytes and TNF-a play a Janus-faced role in anti-PD-L1 therapy-mediated CTL stimulation. This was endorsed by the observation that monocytes appeared crucial to effectively boost T cell-mediated LLC killing in vitro upon combined PD-L1 with LAG-3 or SIRP-a blockade. Hence, this study enlightens the biomarker potential of lung tumor-infiltrated monocytes to define more effective ICB combination strategies. [--]
Materias
Anti-PD-L1 immunotherapy,
Immunotherapy resistance,
Non small cell lung cancer (NSCLC),
TNF-a,
Tumor-infiltrating myeloid cells
Editor
Frontiers Media
Publicado en
Frontiers in Immunology, 2022, 13:811867
Departamento
Universidad Pública de Navarra. Departamento de Ciencias de la Salud /
Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
Versión del editor
Entidades Financiadoras
This research was performed with the financial support of the Research Foundation-Flanders (FWO-V, grant 1515718N, FWO-SBO, grant S004317N and FWO Junior Research, grant G041721N), Wetenschappelijk Fonds Willy Gepts of the UZ Brussel, and Kom op tegen Kanker, the Flemish Cancer Society. RMA, YDV and TE received an FWO-SB fellowship. LDB received an FWO-V fellowship. MK is senior clinical investigator at FWO-V. MIZ was funded by a PhD scholarship from Universidad Pública de Navarra, Pamplona (Spain) and DE is funded by Gobierno de Navarra (project BMED 050-2019), ISCIII (FEDER-PI17/02119, FEDER-PI20/00010) and AECC (PROYE16001ESCO). CG is funded by the Research Council of the Vrije Universiteit Brussel (OZR).
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