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1.
Sci Immunol ; 9(95): eadi5374, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758808

RESUMO

The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.


Assuntos
Microbioma Gastrointestinal , Imunoterapia , Macrófagos , Glicoproteínas de Membrana , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1 , Receptores Imunológicos , Animais , Receptores Imunológicos/imunologia , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Camundongos , Microbioma Gastrointestinal/imunologia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Macrófagos/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos Knockout , Feminino , Intestinos/imunologia
2.
Immunity ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38821051

RESUMO

Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8+ and CD4+ T cells, respectively. Recent studies have unveiled cDC2 heterogeneity and identified various cDC2 progenitors beyond the common DC progenitor (CDP), hinting at distinct cDC2 lineages. By generating Cd300ciCre-hCD2R26tdTomato reporter mice, we identified a bone marrow pro-cDC2 progenitor exclusively generating cDC2 in vitro and in vivo. Single-cell analyses and multiparametric flow cytometry demonstrated that pro-cDC2 encompasses myeloid-derived pre-cDC2 and lymphoid-derived plasmacytoid DC (pDC)-like precursors differentiating into a transcriptionally convergent cDC2 phenotype. Cd300c-traced cDC2 had distinct transcriptomic profiles, phenotypes, and tissue distributions compared with Ms4a3CreR26tdTomato lineage-traced DC3, a monocyte-DC progenitor (MDP)-derived subset that bypasses CDP. Mice with reduced Cd300c-traced cDC2 showed impaired humoral responses to T cell-dependent antigens. We conclude that progenitors of distinct lineages shape the diversity of mature cDC2 across tissues. Thus, ontogenesis may impact tissue immune responses.

3.
Vaccines (Basel) ; 10(6)2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35746551

RESUMO

Tumor-associated macrophages (TAMs) represent a key component of the tumor microenvironment and are generally associated with immunosuppression and poor prognosis. TREM2 is a transmembrane receptor of the immunoglobulin superfamily expressed in myeloid cells. TREM2 has been extensively studied in microglia and neurodegenerative diseases and recently emerged as a marker of pro-tumorigenic macrophages. The accumulation of TREM2-expressing TAMs was reported across numerous cancer patients and tumor models. TREM2 genetic blockade or TREM2 targeting with antibodies resulted in improved tumor control, enhanced response to anti-PD1, and significant changes in the tumor immune landscape. Preclinical studies paved the way for an ongoing clinical trial with a TREM2 depleting antibody and inspired further exploration of TREM2 targeting therapies. Here, we review the current knowledge about the impact of TREM2 in cancer, with an emphasis on the TREM2+ macrophage signature across different cancer types, the contribution of TREM2 to TAM phenotype and function, and the promising effects of TREM2 modulation.

4.
Metallomics ; 11(12): 1999-2009, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31555793

RESUMO

In this work we have demonstrated that the ruthenium nitrosyl complex [RuNO(ß-Pic)2(NO2)2OH] is suitable for investigation of the inactivation of DNA repair enzymes in vitro. Photoinduced inhibition of DNA glycosylases such as E. coli Endo III, plant NtROS1, mammalian mNEIL1 and hNEIL2 occurs to an extent of ≥90% after irradiation with the ruthenium complex. The photophysical and photochemical processes of [RuNO(ß-Pic)2(NO2)2OH] were investigated using stationary and time-resolved spectroscopy, and mass spectrometry. A possible mechanism of the photo-processes was proposed from the combined spectroscopic study and DTF calculations, which reveal that the photolysis is multistage. The primary and secondary photolysis stages are the photo-induced cleavage of the Ru-NO bond with the formation of a free nitric oxide and RuIII complex followed by ligand exchange with solvent. For E. coli Endo III, covalent interaction with the photolysis product was confirmed by UV-vis and mass spectrometric methods.


Assuntos
DNA Glicosilases/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Óxido Nítrico/química , Rutênio/química , DNA Glicosilases/química , Enzimas Reparadoras do DNA/química , Desoxirribonuclease (Dímero de Pirimidina)/química , Desoxirribonuclease (Dímero de Pirimidina)/metabolismo , Ativação Enzimática/efeitos da radiação , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Espectrometria de Massas/métodos , Processos Fotoquímicos/efeitos da radiação , Fotólise/efeitos da radiação , Espectrofotometria/métodos
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