Back to Search
Start Over
Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Feb 01; Vol. 25 (3), pp. 1036-1049. Date of Electronic Publication: 2018 Oct 16. - Publication Year :
- 2019
-
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.<br />Experimental Design: The role of PIM kinases in T cells was studied either by genetic ablation (PIM1 <superscript>-/-</superscript> PIM2 <superscript>-/-</superscript> PIM3 <superscript>-/-</superscript> ) 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.<br />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.<br />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.<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Animals
Antibodies immunology
Antibodies pharmacology
Cell Line, Tumor
Humans
Mice, Inbred C57BL
Mice, Knockout
Neoplasms, Experimental immunology
Neoplasms, Experimental metabolism
Programmed Cell Death 1 Receptor immunology
Programmed Cell Death 1 Receptor metabolism
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-pim-1 genetics
Proto-Oncogene Proteins c-pim-1 metabolism
T-Lymphocytes metabolism
Treatment Outcome
Biphenyl Compounds pharmacology
Immunotherapy, Adoptive methods
Neoplasms, Experimental therapy
Programmed Cell Death 1 Receptor antagonists & inhibitors
Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors
T-Lymphocytes immunology
Thiazolidines pharmacology
Xenograft Model Antitumor Assays methods
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 25
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 30327305
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-18-0706