Exploring the Novel Functions of Cyclin Ds in T Cells and Tumor Progression

SUMMARY/ABSTRACT Poor T-cell tumor trafficking/infiltration and low T-cell survival in the harsh tumor microenvironment (TME) are two critical challenges for the success of T-cell-based immunotherapy against solid tumors. Thus, determining the novel intrinsic mechanism(s) that regulate T-cell infiltration and survival is critical to developing efficient immunotherapy strategies for treating solid tumors. D-type cyclins (D1, D2, and D3) bind cyclin-dependent kinases 4 and 6 (CDK4/6), and the activity of cyclin D/CDK complexes promotes entry into the cell cycle. Cyclin Ds carry out CDK4/6 kinase-dependent and kinase-independent functions. T cells primarily express cyclin D2 and D3. The CDK4/6 kinase-dependent functions of cyclin Ds in T cells were recently reported, but their kinase- independent functions in T cells are not well defined. This study revealed that cyclin D3 deletion in T cells suppressed colorectal tumor growth. Our data indicates that the increased T-cell survival and T-cell tumor infiltration of D3-deleted T cells is due to its kinase-independent function. intracellular cholesterol Sufficient prevents T-cell apoptosis in the harsh solid tumor microenvironment. RNA-seq analysis showed that genes functioning in cholesterol homeostasis were upregulated in D3-deleted T cells. In vitro studies showed that kinase-independent cyclin D3 decreased PPARG expression, which dominates the expression of genes controlling intracellular cholesterol levels. Thus, Aim 1 will determine the mechanism of how cyclin D3 downregulates intracellular cholesterol levels to decrease T-cell survival, promoting colon cancer progression. Meanwhile, adhesion proteins are critical in T-cell tumor infiltration. Aim 2 will determine the kinase-independent function of cyclin D3 in suppressing adhesion protein expression to inhibit T-cell tumor infiltration. Of note, our study showed that cyclin D2 overexpression decreased the expression of cyclin D3, augmenting T-cell capacity to kill tumor cells. Aim 3 will in vivo evaluate the therapeutic efficacy of cyclin D manipulated adoptive T cells on melanoma and colon cancers. We will manipulate cyclin Ds expression in T cells to assess the anti-solid tumor efficacy of adoptive T-cell therapy. Our overarching hypothesis is that manipulating cyclin D expression in T cells augments solid tumor immunotherapy efficacy by increasing T-cell tumor infiltration and T-cell survival through their kinase-independent functions. Project Number: 1R01CA298320-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Haizhen Wang (+1 co-PI) | Institution: MEDICAL UNIVERSITY OF SOUTH CAROLINA, CHARLESTON, SC | Award Amount: $643,053 | Activity Code: R01 | Study Section: Cellular Immunotherapy of Cancer Study Section[CIC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11319447