Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response.
Clin Cancer Res
; 25(3): 1036-1049, 2019 02 01.
Article
em En
| MEDLINE
| ID: mdl-30327305
ABSTRACT
PURPOSE:
Adoptive T-cell therapy (ACT) of cancer, which involves the infusion of ex vivo-engineered tumor epitope reactive autologous T cells into the tumor-bearing host, is a potential treatment modality for cancer. However, the durable antitumor response following ACT is hampered either by loss of effector function or survival of the antitumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the antitumor T cells are of immense importance. Given the role of metabolism in determining the therapeutic efficacy of T cells, we hypothesize that inhibition of PIM kinases, a family of serine/threonine kinase that promote cell-cycle transition, cell growth, and regulate mTORC1 activity, can improve the potency of T cells in controlling tumor. EXPERIMENTALDESIGN:
The role of PIM kinases in T cells was studied either by genetic ablation (PIM1-/-PIM2-/-PIM3-/-) or its pharmacologic inhibition (pan-PIM kinase inhibitor, PimKi). Murine melanoma B16 was established subcutaneously and treated by transferring tumor epitope gp100-reactive T cells along with treatment regimen that involved inhibiting PIM kinases, anti-PD1 or both.RESULTS:
With inhibition of PIM kinases, T cells had significant reduction in their uptake of glucose, and upregulated expression of memory-associated genes that inversely correlate with glycolysis. In addition, the expression of CD38, which negatively regulates the metabolic fitness of the T cells, was also reduced in PimKi-treated cells. Importantly, the efficacy of antitumor T-cell therapy was markedly improved by inhibiting PIM kinases in tumor-bearing mice receiving ACT, and further enhanced by adding anti-PD1 antibody to this combination.CONCLUSIONS:
This study highlights the potential therapeutic significance of combinatorial strategies where ACT and inhibition of signaling kinase with checkpoint blockade could improve tumor control.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Compostos de Bifenilo
/
Linfócitos T
/
Imunoterapia Adotiva
/
Ensaios Antitumorais Modelo de Xenoenxerto
/
Proteínas Proto-Oncogênicas c-pim-1
/
Tiazolidinas
/
Receptor de Morte Celular Programada 1
/
Neoplasias Experimentais
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Clin Cancer Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2019
Tipo de documento:
Article