Canale, Fernando PFernando PCanaleNeumann, JuliaJuliaNeumannvon Renesse, JanuszJanuszvon RenesseLoggi, ElisabettaElisabettaLoggiPecoraro, MatteoMatteoPecoraroVogel, IanIanVogelZoppi, GiadaGiadaZoppiAntonini, GaiaGaiaAntoniniWolf, TobiasTobiasWolfJin, WenjieWenjieJinZheng, XiaoqinXiaoqinZhengLa Barba, GiulianoGiulianoLa BarbaBirgin, EmrullahEmrullahBirginForkel, MarianneMarianneForkelNilsson, TobiasTobiasNilssonMarone, RominaRominaMaroneMueller, HenrikHenrikMuellerPelletier, NadegeNadegePelletierJeker, Lukas TLukas TJekerCivenni, GianlucaGianlucaCivenniSchlapbach, ChristophChristophSchlapbachCatapano, Carlo VCarlo VCatapanoSeifert, LenaLenaSeifertSeifert, Adrian MAdrian MSeifertGillessen, SilkeSilkeGillessenDe Dosso, SaraSaraDe DossoCristaudi, AlessandraAlessandraCristaudiRahbari, Nuh NNuh NRahbariErcolani, GiorgioGiorgioErcolaniGeiger, RogerRogerGeiger2024-10-252024-10-252023-06-14https://boris-portal.unibe.ch/handle/20.500.12422/168298Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well as monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their anti-tumor activity synergistically with PD-L1 blockade in mouse models. Our data reveal new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer.enCRISPR in mouse T cells HCC NK cells T cells cancer immunotherapy liver cancer macrophages mass spectrometry-based proteomics profiles of tumor-infiltrating immune cells proteomes600 - Technology::610 - Medicine & healtharticle10.48350/1842943738891810.1016/j.xgen.2023.100331