Zuazo Ibarra, MirenRidder, Kirsten deLocy, HannePiccioni, ElisaAwad, Robin MaximilianVerhulst, StefaanVan Bulck, MathiasVlaeminck, Yannick deLecoq, QuentinReijimen, EvaMey, Wout deBeck, Lien deErtveldt, ThomasPintelon, IsabelTimmermans, Jean-PierreEscors Murugarren, DavidKeyaerts, MarleenBreckpot, KarineGoyvaerts, Cleo2022-07-212022-07-212022De 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. 13,1664-322410.3389/fimmu.2022.811867https://academica-e.unavarra.es/handle/2454/43383Immune 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.application/pdfeng© 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).Anti-PD-L1 immunotherapyImmunotherapy resistanceNon small cell lung cancer (NSCLC)TNF-aTumor-infiltrating myeloid cellsinfo:eu-repo/semantics/article2022-06-30info:eu-repo/semantics/openAccess