Peripheral-derived regulatory T cells contribute to tumor-mediated immune suppression in a nonredundant manner.
Proc Natl Acad Sci U S A
; 121(36): e2404916121, 2024 Sep 03.
Article
en En
| MEDLINE
| ID: mdl-39207730
ABSTRACT
Identifying tumor-mediated mechanisms that impair immunity is instrumental for the design of new cancer therapies. Regulatory T cells (Tregs) are a key component of cancer-derived immune suppression; however, these lymphocytes are necessary to prevent systemic autoimmunity in mice and humans, and thus, direct targeting of Tregs is not a clinical option for cancer patients. We have previously demonstrated that excising transcription factor Kruppel-like factor 2 (Klf2) within the T cell lineage blocks the generation of peripheral-derived Tregs (pTregs) without impairing production of thymic-derived Tregs. Using this mouse model, we have now demonstrated that eliminating pTregs is sufficient to delay/prevent tumor malignancy without causing autoimmunity. Cancer-bearing mice that expressed KLF2 converted tumor-specific CD4+ T cells into pTregs, which accumulated in secondary lymphoid organs and impaired further T cell effector activity. In contrast, pTreg-deficient mice retained cancer-specific immunity, including improved T cell infiltration into "cold" tumors, reduced T cell exhaustion in tumor beds, restricted generation of tumor-associated myeloid-derived suppressor cells, and the continued production of circulating effector T cells that arose in a cancer-dependent manner. Results indicate that tumor-specific pTregs are critical for early stages of cancer progression and blocking the generation of these inhibitory lymphocytes safely delays/prevents malignancy in preclinical models of melanoma and prostate cancer.
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MEDLINE
Asunto principal:
Linfocitos T Reguladores
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Factores de Transcripción de Tipo Kruppel
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2024
Tipo del documento:
Article