Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response

Clin Cancer Res. 2019 Feb 1;25(3):1036-1049. doi: 10.1158/1078-0432.CCR-18-0706. Epub 2018 Oct 16.


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.

Experimental design: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Biphenyl Compounds / pharmacology*
  • Cell Line, Tumor
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / therapy*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Proto-Oncogene Proteins c-pim-1 / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Thiazolidines / pharmacology*
  • Treatment Outcome
  • Xenograft Model Antitumor Assays / methods*


  • AZD1208
  • Antibodies
  • Biphenyl Compounds
  • Programmed Cell Death 1 Receptor
  • Protein Kinase Inhibitors
  • Thiazolidines
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim