TNF-α-secreting tumor-infiltrated monocytes play a pivotal role during anti-PD-L1 immunotherapy

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dc.contributor.authorZuazo Ibarra, Miren
dc.contributor.authorRidder, Kirsten de
dc.contributor.authorLocy, Hanne
dc.contributor.authorPiccioni, Elisa
dc.contributor.authorAwad, Robin Maximilian
dc.contributor.authorVerhulst, Stefaan
dc.contributor.authorVan Bulck, Mathias
dc.contributor.authorVlaeminck, Yannick de
dc.contributor.authorLecoq, Quentin
dc.contributor.authorReijimen, Eva
dc.contributor.authorMey, Wout de
dc.contributor.authorBeck, Lien de
dc.contributor.authorErtveldt, Thomas
dc.contributor.authorPintelon, Isabel
dc.contributor.authorTimmermans, Jean-Pierre
dc.contributor.authorEscors Murugarren, David
dc.contributor.authorKeyaerts, Marleen
dc.contributor.authorBreckpot, Karine
dc.contributor.authorGoyvaerts, Cleo
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.funderUniversidad Pública de Navarra / Nafarroako Unibertsitate Publikoaes
dc.contributor.funderGobierno de Navarra / Nafarroako Gobernuaes
dc.date.accessioned2022-07-21T06:23:39Z
dc.date.available2022-07-21T06:23:39Z
dc.date.issued2022
dc.date.updated2022-06-30T11:50:34Z
dc.description.abstractImmune 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.en
dc.description.sponsorshipThis 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).en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationDe Ridder, K.; Locy, H.; Piccioni, E.; Zuazo-Ibarra, M.; Awad, R. M.; Verhulst, S.; Van Bulck, M.; De Vlaeminck, Y.; Lecocq, Q.; Reijmen, E.; De Mey, W.; De Beck, L.; Ertveldt, T.; Pintelon, I.; Timmermans, J. P.; Escors, D.; Keyaerts, M.; Breckpot, K.; Goyvaerts, C. (2022). TNF-¿-secreting lung tumor-infiltrated monocytes play a pivotal role during anti-PD-L1 immunotherapy. FRONTIERS IN IMMUNOLOGY. 13,en
dc.identifier.doi10.3389/fimmu.2022.811867
dc.identifier.issn1664-3224
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/43383
dc.language.isoengen
dc.publisherFrontiers Mediaen
dc.relation.ispartofFrontiers in Immunology, 2022, 13:811867en
dc.relation.publisherversionhttps://doi.org/10.3389/fimmu.2022.811867
dc.rights© 2022 De Ridder, Locy, Piccioni, Zuazo, Awad, Verhulst, Van Bulck, De Vlaeminck, Lecocq, Reijmen, De Mey, De Beck, Ertveldt, Pintelon, Timmermans, Escors, Keyaerts, Breckpot and Goyvaerts. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnti-PD-L1 immunotherapyen
dc.subjectImmunotherapy resistanceen
dc.subjectNon small cell lung cancer (NSCLC)en
dc.subjectTNF-aen
dc.subjectTumor-infiltrating myeloid cellsen
dc.titleTNF-α-secreting tumor-infiltrated monocytes play a pivotal role during anti-PD-L1 immunotherapyen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication193d800d-c38c-4627-b9d8-d29435d8214c
relation.isAuthorOfPublication.latestForDiscovery193d800d-c38c-4627-b9d8-d29435d8214c

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