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Targeting Pim2 Improves Effector Function and Longevity of CD8 T cells in Cancer Immunotherapy

ABSTRACT: The Pim kinase family is critically involved in tumorigenesis, yet its function in primary T cells remains poorly understood. We previously reported that Pim2 negatively regulates T-cell responses to alloantigen. To investigate how Pim2 impacts anti-tumor immunity of CD8 T cells, we generated Pim2-/- strains bearing tumor-antigen-specific T cells and performed adoptive T-cell therapy (ACT) against established tumor. We found that Pim2 restricts effector differentiation and persistence of CD8 T cells. As a result, Pim2-/- CD8 T cells exhibited greater potency than WT cells in controlling tumor growth across various cancer models. Mechanistically, Pim2 phosphorylates and inhibits its downstream target Vprbp, a kinase that phosphorylates and stabilizes Ezh2. Consistently, Pim2 deficiency increased Ezh2 expression and H3K27 trimethylation in CD8 T cells. Elevated Ezh2 activity in Pim2-/- CD8 T cells supported progenitor-like/memory differentiation within lymphoid organs. Furthermore, Pim2 deficiency diminished autophagy in CD8 T cells, thereby promoting glycolytic metabolism to drive effector T-cell differentiation in the tumor microenvironment (TME). In human T cells, silencinge Pim2 increased cytokine production and effector differentiation. A Pim2-specific inhibitor improved murine T-cell immunity against melanoma and increased the activity of human melanoma-specific T cells and CD19 CAR-T cells. Taken together, the current work reveals novel and compelling evidence to support Pim2 as a promising therapeutic target for improving cancer immunotherapy through enhancing effector differentiation and persistence of T cells.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, T Cell

SUBMITTER: Jennifer Bethard

LAB HEAD: Xue-Zhong Yu

PROVIDER: PXD059837 | Pride | 2026-01-08

REPOSITORIES: Pride

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			Action	DRS
	06072023_Wu_TotalProtein_F1.raw	Raw
	06072023_Wu_TotalProtein_F10.raw	Raw
	06072023_Wu_TotalProtein_F11.raw	Raw
	06072023_Wu_TotalProtein_F12.raw	Raw
	06072023_Wu_TotalProtein_F2.raw	Raw

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Project description:The optimal T cell attributes for the adoptive immunotherapy of cancer and viral diseases are currently unclear. Recent adoptive transfer clinical trials using ex vivo expanded tumor infiltrating lymphocytes has provided evidence that differentiated effector T cells can mediate durable responses in selected cancer patients. The capacity of these transferred cells to persist in the host was found to strongly correlate with their clinical activity. Thus, there is significant interest in identifying intrinsic markers that define antigen specific effector T cells that can develop into long-lived memory cells rather than undergoing apoptosis after infusion in humans. We recently reported the long term persistence of ex vivo expanded tumor specific CD8+ T effector clones in refractory metastatic melanoma patients after adoptive T cell transfer. By utilizing these highly homogeneous clone populations, we sought to define the pre-infusion cellular and molecular attributes associated with their effector to memory transition. Comparative transcriptional profiling found the pre-infusion clone mRNA expression levels of the IL-7 receptor (IL-7Ra) and the proto-oncogene, c-myc, directly correlated with the level of clonal persistence after adoptive transfer in humans. The predictive value of these markers was further established by utilizing IL-7R protein, induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor specific effector clones that could engraft after controlled adoptive transfer into highly immunodeficient mice. These findings support that IL-7R and c-myc expression are valuable cell intrinsic markers that can predict the fate of effector CD8+ T cells after adoptive transfer. We used microarrays to compare the pre-infusion gene expression profile of melanoma-specific CD8+ T cell clones that would eventually either persist or not after adoptive transfer in humans. We derived ten melanoma-specific CD8+ T cell clones and determined their degree of persistence after adoptive therapy into patients. We performed microarray on the pre-infusion samples of six persisting and four non-persisting clones to obtain a comparative gene signature profile.

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Targeting Pim2 Improves Effector Function and Longevity of CD8 T cells in Cancer Immunotherapy

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