CDK4/6 inhibitors sensitize gammaherpesvirus-infected tumor cells to T-cell killing by enhancing expression of immune surface molecules.

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.

Dogs ≥ five years of age at the time of congenital extrahepatic portosystemic shunt diagnosis have better long-term outcomes with surgical attenuation than with medical management alone.

OBJECTIVE: To determine the outcome in dogs diagnosed with congenital extrahepatic portosystemic shunts (EHPSS) at ≥ 5 years of age treated with medical management only (M) or with surgical attenuation (S). The hypothesis was that dogs undergoing surgical attenuation would have a longer survival time than dogs undergoing medical management only. ANIMALS: 351 dogs definitively diagnosed with EHPSS at ≥ 5 years of age. PROCEDURES: Medical records from 2009 to 2019 at 16 veterinary teaching hospitals were evaluated. Data collected included signalment, clinical signs at diagnosis, clinicopathologic data, surgical and medical treatments, shunt morphology, clinical signs and medical treatments at 6 to 12 months after diagnosis, and survival time. RESULTS: 351 dogs (M, 119 [33.9%]; S, 232 [66.1%]) were included in the study. Survival time was longer with surgery than medical management (hazard ratio, 4.2; M, 3.4 years; S, 10.9 years). Continued clinical signs at 6 to 12 months after diagnosis were more common with medical management (M, 40% [33/88]; S, 14% [21/155]). Continued medical treatments at 6 to 12 months after diagnosis were more common in the medical management group (M, 78% [69/88]; S, 34% [53/155]). Perioperative mortality rate was 7.3%. CLINICAL RELEVANCE: Dogs diagnosed at ≥ 5 years of age with EHPSS have significantly better survival times and fewer clinical signs with surgical attenuation, compared with medical management. Older dogs have similar surgical mortality rates to dogs of all ages after surgical EHPSS attenuation.