Liver Metastasis Modulate Responses of Suppressive Macrophages and Exhausted T Cells to Immunotherapy Revealed by Single Cell Sequencing.
Adv Genet (Hoboken)
; 3(4): 2200002, 2022 Dec.
Article
en En
| MEDLINE
| ID: mdl-36911291
ABSTRACT
Liver metastasis is associated with immunotherapy resistance, although the underlying mechanisms remain incompletely understood. By applying single cell RNA-sequencing to a concurrent subcutaneous and liver tumor murine model to recapitulate liver metastases, it is identified that subsets within tumor-infiltrating exhausted CD8+ T (Tex) cells and immunosuppressive tumor-associated macrophages (TAMs) display opposite responses to concurrent liver tumors and anti-PD-1 treatment, suggesting a complex immune regulating network. Both angiogenic and interferon-reactive TAMs show increased frequencies in implanted liver tumors, and anti-PD-1 treatment further elevates the frequencies of angiogenic TAMs. Such TAMs frequencies negatively correlate with the proportions of cytotoxic T cell subsets. Further, expression of interferon-stimulated genes in TAMs is dramatically reduced under effective anti-PD-1 treatment, while such tendencies are diminished in mice with implanted liver tumors. Therefore, the study indicates that liver metastases could increase immunosuppressive TAMs frequencies and inhibit Tex responses to PD-1 blockade, resulting in compromised systemic antitumor immunity and limited immunotherapy efficacy.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Idioma:
En
Revista:
Adv Genet (Hoboken)
Año:
2022
Tipo del documento:
Article