Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA.
Commun Biol
; 4(1): 906, 2021 07 23.
Article
em En
| MEDLINE
| ID: mdl-34302042
ABSTRACT
Expressed on cells of the myeloid and lymphoid lineages, V-domain Ig Suppressor of T cell Activation (VISTA) is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. Using a tripeptide small molecule antagonist of VISTA CA170, we found that it exhibited potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHCII-directed KRAS peptide vaccine. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 increased CD8+ T cell infiltration and enhanced their effector functions by decreasing the tumor infiltration of myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells, while the Kras vaccine primarily induced expansion of CD4+ effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and drives an adaptive T cell tumor-specific immune response that enhances the efficacy of the KRAS vaccine.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinogênese
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Pulmão
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Neoplasias Pulmonares
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Proteínas de Membrana
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article