Accumulation of MDSC subsets in renal cell carcinoma correlates with grade and progression free survival, and is associated with intratumoral expression of IL-1β, IL-8 and CXCL5

Myeloid derived suppressor cells (MDSC, CD33+CD11b+ HLA-DR low/-) play a major role in tumor-mediated immune evasion and are composed of at least 3 subsets PMN (CD15+), monocytic (CD14+) and lineage-negative (CD15-CD14-), and each has been shown to be significantly increased in some human tumor types and to correlate with metastatic burden, clinical cancer stage and outcome. Less in known about the MDSC subsets that accumulate in tumors such as renal cell carcinoma (RCC) and the cytokines/chemokines involved in their recruitment. Flow cytometry analysis of peripheral blood mononuclear cells (PBMC, n = 20) and nephrectomy samples (n = 39, stage 1-4) showed increased levels of total MDSC in RCC patients compared to normal controls (n = 15), with PMN- and Lin- MDSC subsets dominating in the blood and tumor of RCC patients. Blood levels of total MDSC, PMN-MDSC and Lin-MDSC correlated with tumor grade (p = 0.026, p = 0.006 and p = 0.045, respectively), while blood levels of total MDSC and Lin-MDSC correlated with progression free survival (PFS) in patients with limited stage disease (n = 16, stages 1-3) (HR = 1.35, p = 0.03; HR = 1.45, p = 0.02, respectively). In the tumor, higher PMN-MDSC levels were significantly associated with decreased PFS (n = 29, HR = 1.09, p = 0.011). To assess the role of select chemokines (IL-8, CXCL5, Mip-1α, MCP-1 and Rantes) and of the pro-inflammatory cytokine IL-1β in promoting the accumulation of MDSC within the tumor, these proteins were quantitated in tumor lysates by ELISA and correlated to MDSC frequencies (Spearman correlations). We found a direct correlation between the frequency of PMN-MDSC in the parenchyma and the levels of IL-8 (p < 0.001), CXCL-5 (p < 0.001), and IL-1β (p = 0.029). Frequency of parenchymal Lin- MDSC directly correlated with levels of IL-8 (p = 0.033) and CXCL-5 (p = 0.008), but not IL-1β. In circulation, frequency of total MDSCs directly correlated with IL-1β plasma levels (p = 0.003).\ud \ud To further define the role of IL-1β in MDSC accumulation within tumors, we overexpressed IL-1β in RENCA and CT26 tumors and compared them to untransfected tumors. Overexpression of IL-1β resulted in enhanced tumor growth and increased frequency of intratumor PMN-MDSC (10.3X in RENCA and 26X in CT26), with a modest increase in intratumor M-MDSC. A large fraction of tumor infiltrating PMN-MDSC expressed CXCR2 (84% in RENCA and 55% in CT26), which is associated with a significant increase in expression of CXCR2 ligands (KC, CXCL5, and MIP2). These results support the idea that IL-1β-mediated induction of select chemokines promotes the accumulation of MDSC, particularly PMN-MDSC, within tumors, resulting in enhanced immune suppression and angiogenesis

Selenium, Selenoenzymes, Oxidative Stress and Risk of Neoplastic Progression from Barrett's Esophagus: Results from Biomarkers and Genetic Variants

Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA) and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX) 1 and GPX3 by substrate-specific coupled test procedures, selenoprotein P (SEPP1) concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend = 0.25 to 0.85). SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR) = 3.95, 95% confidence intervals (CI) = 1.42–10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31–32.58), but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p = 0.12–0.69). Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1 concentrations with the risk of EA and aneuploidy, which warrants further investigation

Sustained silver-releasing dressing in the treatment of diabetic foot ulcers

This study investigated the clinical performance and safety of a sustained silver-releasing foam dressing, Contreet Foam, in the treatment of diabetic foot ulcers. Twenty-seven patients with diabetic foot ulcers of grade I or II (Wagner's classification) were followed for six weeks: one week run-in using Biatain dressings, four weeks' treatment with Contreet dressings. Four ulcers healed during the four-week treatment with Contreet 56% in average. Contreet Foam showed good exudate management properties and was considered easy to use. Only two infections occurred showed that all six of the non-study ulcers developed an infection during the study. All ulcers (study ulcers as well as non-study ulcers) were treated according to good practice of diabetic wound care. There were no directions for the treatment of secondary wounds. No device-related adverse events were observed. This study demonstrated that Contreet Foam is safe and easy to use and effectively supports healing and good wound progress of diabetic foot ulcers

Sustained silver-releasing dressing in the treatment of diabetic foot ulcers

This study investigated the clinical performance and safety of a sustained silver-releasing foam dressing, Contreet Foam, in the treatment of diabetic foot ulcers. Twenty-seven patients with diabetic foot ulcers of grade I or II (Wagner's classification) were followed for six weeks: one week run-in using Biatain dressings, four weeks' treatment with Contreet dressings. Four ulcers healed during the four-week treatment with Contreet 56% in average. Contreet Foam showed good exudate management properties and was considered easy to use. Only two infections occurred showed that all six of the non-study ulcers developed an infection during the study. All ulcers (study ulcers as well as non-study ulcers) were treated according to good practice of diabetic wound care. There were no directions for the treatment of secondary wounds. No device-related adverse events were observed. This study demonstrated that Contreet Foam is safe and easy to use and effectively supports healing and good wound progress of diabetic foot ulcers

Ifit2 deficiency restricts microglial activation and leukocyte migration following murine coronavirus (m-CoV) CNS infection.

The interferon-induced tetratricopeptide repeat protein (Ifit2) protects mice from lethal neurotropic viruses. Neurotropic coronavirus MHV-RSA59 infection of Ifit2-/- mice caused pronounced morbidity and mortality accompanied by rampant virus replication and spread throughout the brain. In spite of the higher virus load, induction of many cytokines and chemokines in the brains of infected Ifit2-/- mice were similar to that in wild-type mice. In contrast, infected Ifit2-/- mice revealed significantly impaired microglial activation as well as reduced recruitment of NK1.1 T cells and CD4 T cells to the brain, possibly contributing to the lack of viral clearance. These two deficiencies were associated with a lower level of microglial expression of CX3CR1, the receptor of the CX3CL1 (Fractalkine) chemokine, which plays a critical role in both microglial activation and leukocyte recruitment. The above results uncovered a new potential role of an interferon-induced protein in immune protection

Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series

Abstract Background Talimogene Laherparepvec (T-VEC) is an oncolytic virus approved as an intratumoral therapy for treating unresectable stage IIIB-IV metastatic melanoma. The mechanisms of action for T-VEC and checkpoint inhibitor are highly complementary. Recent studies have shown that combining checkpoint inhibitor therapy with T-VEC injection can lead to improved response rates for stage IIIB-IV melanoma patients. Methods We reviewed 10 consecutive cases of stage IIIC to stage IVM1b melanoma patients that received T-VEC plus checkpoint inhibitor(s) therapy (pembrolizumab, ipilimumab/nivolumab, or nivolumab) treated between June 2016 and August 2017 at the Cleveland Clinic with a median follow-up of 7 months (range: 4 to 13 months). Responses of injected (on-target) and uninjected (off-target) lesions were evaluated according to RECIST 2.0. Results The overall response rate for on-target lesions was 90%, with 6 patients experiencing a complete response in injected lesions. Two patients had off-target lesions, which were completely resolved after treatment. Blood samples were tested for 3 complete responders and 2 partial responders. CD4:CD8 ratio and frequencies of circulating PD1+ CD4 and CD8 T cells were elevated in complete responders but not partial responders. One patient died due to causes unrelated to melanoma and one patient died of progression of the disease. Conclusion Our data suggest that combining checkpoint inhibitor(s) with T-VEC injection may provide a synergistic efficacy for patients with unresectable melanoma. We observed a better overall response rate and complete response rate compared to published studies on similar therapeutic regimens