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Published on: May 27, 2011
CDK4/6 inhibitors sensitize gammaherpesvirus-infected tumor cells to T-cell killing by enhancing expression of immune
Yiquan Wu1, Prabha Shrestha1, Natalie M Heape1
1HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Building 10, Rm. 6N106, MSC 1868, 10 Center Drive, Bethesda, MD, 20892-1868, USA.
Background:
The two oncogenic human gammaherpesviruses, Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), both downregulate immune surface molecules, such as MHC-I, ICAM-1, and B7-2, enabling them to evade T-cell and natural killer cell immunity. Both also either encode for human cyclin homologues or promote cellular cyclin activity, and this has been shown to be important for proliferation and survival of gammaherpesvirus-induced tumors. CDK4/6 inhibitors, which are approved for certain breast cancers, have been shown to enhance expression of MHC-I in cell lines and murine models of breast cancer, and this was attributed to activation of interferons by endogenous retrovirus elements. However, it was not known if this would occur in gammaherpesvirus-induced tumors in which interferons are already activated.
Methods:
Multiple KSHV/EBV-infected cell lines were treated with CDK4/6 inhibitors. The growth of viable cells and expression of surface markers was assessed. T cell activation stimulated by the treated cells was assayed by a T-cell activation bioassay. Both viral and host gene expression was surveyed using RT-qPCR.
Results:
Three CDK4/6 inhibitors, abemaciclib, palbociclib, and ribociclib, inhibited cell growth in KSHV-induced primary effusion lymphoma (PEL) and EBV positive Burkitt's lymphoma (BL) cell lines, and KSHV-infected human umbilical vein endothelial cells (HUVECs). Moreover, CDK4/6 inhibitors increased mRNA and surface expression of MHC-I in all three and prevented downregulation of MHC-I surface expression during lytic replication in KSHV-infected cells. CDK4/6 inhibitors also variably increased mRNA and surface expression of ICAM-1 and B7-2 in the tested lines. Abemaciclib also significantly enhanced T-cell activation induced by treated PEL and BL cells. Certain gammaherpesvirus genes as well as endogenous retrovirus (ERV) 3-1 genes were enhanced by CDK4/6 inhibitors in most PEL and BL lines and this enhancement was associated with expression of gamma interferon-induced genes including MHC-I.
Conclusions:
These observations provide evidence that CDK4/6 inhibitors can induce expression of surface immune markers MHC-I, B7-2, and ICAM-1 in gammaherpesvirus-infected cell lines and induce virus-specific immunity. They can thus thwart virus-induced immune evasion. These effects, along with their direct effects on KSHV- or EBV-induced tumors, provide a rational for the clinical testing of these drugs in these tumors.
Insights
CDK4/6 inhibitors restore immune evasion in gammaherpesvirus-infected cells by increasing MHC-I expression. This suggests potential for clinical testing in Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus-driven tumors.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Human gammaherpesviruses, Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), evade immune responses by downregulating immune surface molecules like MHC-I, ICAM-1, and B7-2.
- These viruses also promote cell proliferation and survival through cyclin activity, contributing to tumor development.
- CDK4/6 inhibitors, used in breast cancer treatment, have shown potential to enhance MHC-I expression, but their effect in gammaherpesvirus-induced tumors with existing interferon activation was unknown.
Purpose of the Study:
- To investigate the efficacy of CDK4/6 inhibitors in restoring immune recognition of gammaherpesvirus-infected cells.
- To determine if CDK4/6 inhibitors can overcome immune evasion mechanisms employed by KSHV and EBV.
- To assess the impact of CDK4/6 inhibitors on immune surface marker expression and T-cell activation in relevant cancer models.
Main Methods:
- Treatment of KSHV/EBV-infected cell lines with CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib).
- Assessment of cell viability and surface marker expression.
- Assay of T-cell activation using a bioassay and evaluation of viral and host gene expression via RT-qPCR.
Main Results:
- CDK4/6 inhibitors reduced cell growth in primary effusion lymphoma (PEL), Burkitt's lymphoma (BL), and KSHV-infected endothelial cells.
- Treatment increased mRNA and surface expression of MHC-I, ICAM-1, and B7-2, preventing MHC-I downregulation during KSHV lytic replication.
- Abemaciclib enhanced T-cell activation by treated PEL and BL cells, with associated upregulation of interferon-gamma-induced genes.
Conclusions:
- CDK4/6 inhibitors can restore expression of immune surface markers (MHC-I, B7-2, ICAM-1) in gammaherpesvirus-infected cells, thereby countering virus-induced immune evasion.
- These findings provide a rationale for clinical trials of CDK4/6 inhibitors in KSHV- and EBV-driven tumors, leveraging both direct anti-tumor effects and immune modulation.
- The study highlights the potential of CDK4/6 inhibitors to re-sensitize gammaherpesvirus-induced tumors to immune surveillance and therapy.
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