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1.
Cell Rep ; 41(10): 111769, 2022 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-36476866

RESUMEN

Monocytes are highly plastic immune cells that modulate antitumor immunity. Therefore, identifying factors that regulate tumor monocyte functions is critical for developing effective immunotherapies. Here, we determine that endogenous cancer cell-derived type I interferons (IFNs) control monocyte functional polarization. Guided by single-cell transcriptomic profiling of human and mouse tumors, we devise a strategy to distinguish and separate immunostimulatory from immunosuppressive tumor monocytes by surface CD88 and Sca-1 expression. Leveraging this approach, we show that cGAS-STING-regulated cancer cell-derived IFNs polarize immunostimulatory monocytes associated with anti-PD-1 immunotherapy response in mice. We also demonstrate that immunosuppressive monocytes convert into immunostimulatory monocytes upon cancer cell-intrinsic cGAS-STING activation. Consistently, we find that human cancer cells can produce type I IFNs that polarize monocytes, and our immunostimulatory monocyte gene signature is enriched in patient tumors that respond to anti-PD-1 immunotherapy. Our work exposes a role for cancer cell-derived IFNs in licensing monocyte functions that influence immunotherapy outcomes.


Asunto(s)
Interferón Tipo I , Neoplasias , Humanos , Ratones , Animales , Monocitos
2.
Nat Immunol ; 23(5): 743-756, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35437326

RESUMEN

Phenotypic and transcriptional profiling of regulatory T (Treg) cells at homeostasis reveals that T cell receptor activation promotes Treg cells with an effector phenotype (eTreg) characterized by the production of interleukin-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eTreg cell activity, whereas during infection with Toxoplasma gondii, early interferon-γ upregulates myeloid cell expression of PD-L1 associated with reduced Treg cell populations. In infected mice, blockade of PD-L1, complete deletion of PD-1 or lineage-specific deletion of PD-1 in Treg cells prevents loss of eTreg cells. These interventions resulted in a reduced ratio of pathogen-specific effector T cells: eTreg cells and increased levels of interleukin-10 that mitigated the development of immunopathology, but which could compromise parasite control. Thus, eTreg cell expression of PD-1 acts as a sensor to rapidly tune the pool of eTreg cells at homeostasis and during inflammatory processes.


Asunto(s)
Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , Linfocitos T Reguladores , Toxoplasmosis Animal , Animales , Antígeno B7-H1/inmunología , Homeostasis , Interleucina-10/inmunología , Ratones , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T Reguladores/inmunología , Toxoplasma/inmunología , Toxoplasmosis Animal/inmunología
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