Malignant gliomas are lethal cancers in the brain and heavily infiltrated by myeloid cells. Interleukin-4 receptor-α (IL-4Rα) mediates the immunosuppressive functions of myeloid cells, and polymorphisms in the IL-4Rα gene are associated with altered glioma risk and prognosis. In this study, we sought to evaluate an hypothesized causal role for IL-4Rα and myeloid suppressor cells in glioma development. In both mouse de novo gliomas and human glioblastoma cases, IL-4Rα was upregulated on glioma-infiltrating myeloid cells but not in the periphery or in normal brain. Mice genetically deficient for IL-4Rα exhibited a slower growth of glioma associated with reduced production in the glioma microenvironment of arginase, a marker of myeloid suppressor cells which is critical for their T cell inhibitory function. Supporting this result, investigations using bone marrow-derived myeloid cells showed that IL-4Rα mediates IL-13-induced production of arginase. Furthermore, glioma-derived myeloid cells suppressed T cell proliferation in an IL-4Rα-dependent manner, consistent with their identification as myeloid-derived suppressor cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a central role for the induction of IL-4Rα expression on myeloid cells, and we found that GM-CSF is upregulated in both human and mouse glioma microenvironments compared with normal brain or peripheral blood samples. Together, our findings establish a GM-CSF-induced mechanism of immunosuppression in the glioma microenvironment via upregulation of IL-4Rα on myeloid-derived suppressor cells.

NK cells are effector lymphocytes playing a critical role in the natural resistance against tumors. However, the precise mechanisms underlying NK cell-mediated natural resistance against tumor metastasis are still unrevealed. B16 cells, mouse melanoma cells, were resistant to freshly isolated NK cell-mediated killing; nevertheless, NK cells were critical for natural resistance against experimental lung metastasis of B16 cells. We found that lung metastasis was increased significantly in IFN-γ(-/-) mice but not pfp(-/-), IFN-αR(-/-), or IL-12/IL-18(-/-) mice. Interestingly, freshly isolated lung NK cells, but not spleen or liver NK cells, displayed augmented IFN-γ production after B16 inoculation. Adoptive transfer of pfp(-/-) NK cells, but not IFN-γ(-/-) NK cells, significantly decreased B16 lung metastasis in IFN-γ(-/-) and pfp/IFN-γ(-/-)mice. Lung metastases of IFN-γRDN B16 was also increased in NK cell-depleted or IFN-γ(-/-) mice, suggesting that the IFN-γ response of host cells was required in the NK cell and IFN-γ-mediated antimetastatic effect. Our results demonstrate that IFN-γ production from lung resident NK cells is a key response in the natural resistance to the experimental lung metastasis of NK cell-resistant tumor cells.

PURPOSE WHO grade II low-grade gliomas (LGGs) with high risk factors for recurrence are mostly lethal despite current treatments. We conducted a phase I study to evaluate the safety and immunogenicity of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes in HLA-A2+ adults with high-risk LGGs in the following three cohorts: 1) patients without prior progression, chemotherapy or radiation therapy (RT); 2) patients without prior progression or chemotherapy but with prior RT, and 3) recurrent patients. METHODS GAAs were IL-13Rα2, EphA2, WT1, and Survivin. Synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks for 8 courses with intramuscular injections of poly-ICLC, followed by q12week booster vaccines. RESULTS Cohorts 1, 2, and 3 enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity was encountered except for one case with Grade 3 fever, fatigue and mood disturbance (Cohort 1). ELISPOT assays demonstrated robust IFN-γ responses against at least 3 of the 4 GAA epitopes in 10 and 4 cases of Cohorts 1 and 3, respectively. Cohort 1 patients demonstrated significantly higher IFN-γ responses than Cohort 3 patients. Median progression-free survival (PFS) periods since the 1st vaccine are 17 months in Cohort 1 (range 10–47+) and 12 months in Cohort 3 (range 3–41+). The only patient with large astrocytoma in Cohort 2 has been progression-free for over 67 months since diagnosis. CONCLUSION The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade II glioma patients. These results warrant further evaluations of this approach.

Our results suggest that strong TAA-specific CD8(+) T-cell responses suppress the recurrence of HCC. Immunotherapy to induce TAA-specific cytotoxic T lymphocytes by means such as the use of peptide vaccines should be considered for clinical application in patients with HCC after local therapy.

Intrahepatic Tregs were increased in both patients with autoimmune liver diseases and those with viral hepatitis. In autoimmune liver diseases, intrahepatic Tregs were fewer in the AIH patients than in the PBC patients.

These results suggest that the -1195GG genotype of the COX-2 promoter region protects against HCV infection in the Japanese. However, once chronic infection is established, the -443TT genotype of the OPN promoter region and the -1195GG genotype of the COX-2 promoter are thought to promote inflammation and contribute to the progression of liver disease.

Cyclooxygenase (COX)-2 is involved in inflammation, anti-apoptosis and carcinogenesis. The -1195GG genotype of single nucleotide polymorphism (SNP) in COX-2 promoter was associated with low platelet counts in patients with chronic hepatitis C. Polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene (rs738409 C>G) have been reported to be associated with cirrhosis, and the major genotype of SNPs near interleukin (IL)28B are related to viral clearance. The present study was designed to assess the contribution of these SNPs to disease progression in patients with chronic hepatitis C. The study enrolled 220 Japanese patients with chronic hepatitis C. Three SNPs, -1195 COX-2, PNPLA3 and IL28B (rs8099917), were genotyped in order to analyze their association with hepatic fibrosis and inflammation. The -1195GG genotype in COX-2 was associated with advanced fibrosis and higher levels of inflammation in the liver tissues. The major genotype of IL28B was also associated with advanced fibrosis, but the polymorphism of PNPLA3 was neither associated with fibrosis nor inflammation. Multivariate analysis showed that -1195GG in COX-2 is an independent factor associated with advanced fibrosis, while the major genotype of IL28B and HCV genotype 2 were other independent factors. In conclusion, the -1195GG genotype in COX-2 is a genetic marker for liver disease progression, while the PNPLA3 genotypes are not associated with disease progression in Japanese patients with chronic hepatitis C.

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUC inf) and maximum observed concentration (C max) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUC inf and C max , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.