Exploring the novel functions of cyclin DS in t cells and tumor progression

The National Cancer Institute awarded The Medical University of South Carolina $643,053 on May 1, 2026, under the Cancer Biology Research program (CFDA 93.396) to explore the kinase-independent functions of cyclin D3 in T cells and its effects on tumor progression and immunotherapy efficacy.

The research addresses T-cell poor infiltration and survival in solid tumor microenvironments by investigating how cyclin D3 regulates intracellular cholesterol homeostasis and adhesion protein expression in T cells. Aim 1 determines the mechanism by which cyclin D3 downregulates intracellular cholesterol levels to decrease T-cell survival and promote colon cancer progression. Aim 2 identifies how cyclin D3's kinase-independent function suppresses adhesion protein expression to inhibit T-cell tumor infiltration. Prior work demonstrated that cyclin D3 deletion in T cells suppressed colorectal tumor growth through increased T-cell survival and tumor infiltration, effects attributed to kinase-independent mechanisms rather than cyclin-dependent kinase 4/6 activity.

Performance occurs in Charleston, South Carolina through April 30, 2031. Loyola University of Chicago Health Sciences Campus serves as a sub-recipient, with Dr. Nishimura providing expertise in constructing retroviral and lentiviral vectors to transduce mouse and human T cells, genetically modifying T cells for functional assessment, and supplying genetically modified T cells to the principal investigator for in vivo tumor studies. The sub-award to Loyola was dated August 20, 2026.

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.