Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma.

Adoptive transfer of tumor antigen-specific CD8+ T cells can limit tumor progression but is hampered by the T cells' rapid functional impairment within the tumor microenvironment (TME). This is in part caused by metabolic stress due to lack of oxygen and glucose. Here, we report that fenofibrate treatment of human ex vivo expanded tumor-infiltrating lymphocytes (TILs) improves their ability to limit melanoma progression in a patient-derived xenograft (PDX) mouse model. TILs treated with fenofibrate, a peroxisome proliferator receptor alpha (PPARα) agonist, switch from glycolysis to fatty acid oxidation (FAO) and increase the ability to slow the progression of autologous melanomas in mice with freshly transplanted human tumor fragments or injected with tumor cell lines established from the patients' melanomas and ex vivo expanded TILs.

Heterologous chimpanzee adenovirus vector immunizations for SARS-CoV-2 spike and nucleocapsid protect hamsters against COVID-19.

Available COVID-19 vaccine only provide protection for a limited time due in part to the rapid emergence of viral variants with spike protein mutations, necessitating the generation of new vaccines to combat SARS-CoV-2. Two serologically distinct replication-defective chimpanzee-origin adenovirus (Ad) vectors (AdC) called AdC6 and AdC7 expressing early SARS-CoV-2 isolate spike (S) or nucleocapsid (N) proteins, the latter expressed as a fusion protein within herpes simplex virus glycoprotein D (gD), were tested individually or as a mixture in a hamster COVID-19 SARS-CoV-2 challenge model. The S protein expressing AdC (AdC-S) vectors induced antibodies including those with neutralizing activity that in part cross-reacted with viral variants. Hamsters vaccinated with the AdC-S vectors were protected against serious disease and showed accelerated recovery upon SARS-CoV-2 challenge. Protection was enhanced if AdC-S vectors were given together with the AdC vaccines that expressed the gD N fusion protein (AdC-gDN). In contrast hamsters that just received the AdC-gDN vaccines showed only marginal lessening of symptoms compared to control animals. These results indicate that immune response to the N protein that is less variable than the S protein may potentiate and prolong protection achieved by the currently used S protein based genetic COVID-19 vaccines.

In-vitro immunomodulatory effects of nicotine on Nitric Oxide, interleukin 1ß and interleukin 37 production in human peripheral blood mononuclear cells (PBMC) from patients with Behçet disease.

Behçet's disease is a chronic systemic inflammatory disorder associated with a cytokine profile disruption and increased nitric oxide levels. In our current study we sought to evaluate the in-vitro modulatory effect of nicotine, the principal alkaloid of tobacco, on nitric oxide (NO), interleukin 1ß (IL-1ß) and interleukin 37 (IL-37) production during Behçet's disease. Peripheral blood mononuclear cells cultures were performed with or without nicotine (200 µg/ml). Culture supernatants were harvested after 24 h of incubation. NO, IL-1ß and IL-37 measurements were, respectively, performed by modified Griess method and ELISA sandwich. Our results showed that nicotine significantly reduced NO and IL-1ß levels in patients with Behçet's disease, while it increased IL-37 production. Our results showed no sex differences in the effects of nicotine on the production of nitric oxide and IL-1ß nor IL-37 in PBMC of patients. Our findings suggest that nicotine may provide a potential therapeutic strategy targeting inflammation during Behçet's disease.

PPARα Agonist Fenofibrate Enhances Cancer Vaccine Efficacy.

Reducing metabolic stress within the tumor microenvironment (TME) could be essential for improving the efficacy of cancer immunotherapy. Using a mouse model of melanoma, we show here that appropriately timed treatment with the PPARα agonist fenofibrate improves the ability of a T cell-inducing cancer vaccine to delay tumor progression. Fenofibrate reduced the use of glucose by tumor and stromal cells in the TME and promoted the use of fatty acids for their metabolic needs. The glucose within the TME was in turn available for use by vaccine-induced tumor-infiltrating CD8+ T cells, which improved their ability to slow tumor progression. Early fenofibrate treatment 3 days after vaccination improved functions of circulating CD8+ T cells but failed to significantly affect tumor-infiltrating lymphocyte (TIL) metabolism or decrease tumor progression. In contrast, delaying treatment until day 5 after vaccination modified TIL metabolism and augmented the vaccine's ability to slow tumor progression. In summary, our findings reveal that a PPARα agonist can increase the efficacy of a cancer vaccine by reprogramming cells within tumors to increase fatty acid metabolism, providing T cells access to glucose in the TME. SIGNIFICANCE: These findings suggest that metabolic manipulations using already approved drugs may offer an easy pathway to increase the efficacy of vaccines against solid tumors.

T cell responses to adenoviral vectors expressing the SARS-CoV-2 nucleoprotein.

SARS-CoV-2 vaccines aim to protect against COVID-19 through neutralizing antibodies against the viral spike protein. Mutations within the spike's receptor-binding domain may eventually reduce vaccine efficacy, necessitating periodic updates. Vaccine-induced immunity could be broadened by adding T cell-inducing antigens such as SARS-CoV-2's nucleoprotein (N). Here we describe two replication-defective chimpanzee adenovirus (AdC) vectors from different serotypes expressing SARS-CoV-2 N either in its wild-type form or fused into herpes simplex virus glycoprotein D (gD), an inhibitor of an early T cell checkpoint. The vaccines induce potent and sustained CD8+ T cell responses that are broadened upon inclusion of gD. Depending on the vaccine regimen booster immunizations increase magnitude and breadth of T cell responses. Epitopes that are recognized by the vaccine-induced T cells are highly conserved among global SARS-CoV-2 isolates indicating that addition of N to COVID-19 vaccines may lessen the risk of loss of vaccine-induced protection due to variants.

Uric acid increases IL-1ß secretion and Caspase-1 activation in PBMCs of Behçet's disease patients: The in vitro immunomodulatory effect of xanthine oxidase inhibitor Allopurinol.

Behçet's disease (BD) is a multisystem disease, which shares some features with other diseases belonging to the autoinflammatory disorders panel. Recent studies have postulated that IL-1ß/Caspase-1 may play a cardinal role in autoinflammatory diseases. In this study, we aimed to (i) elucidate the mechanism underlying the involvement of xanthine oxidase (XO) and Uric Acid (UA) in BD (ii) study the direct effects of UA and XO inhibitor "Allopurinol" on nitric oxide (NO) and caspase-1-mediated IL-1ß release in peripheral blood mononuclear cells (PBMCs) of BD patients. In this context, plasma of BD patients and healthy controls (HC) were used to measure XO activity, UA, advanced oxidized proteins products (AOPP) and NO levels. In Addition, PBMCs of BD patients and HC were treated or not with either UA or Allopurinol. Then we quantified NO and IL-1ß levels, and Caspase-1 Activity in the supernatants and lysates of PBMCs, respectively. We showed that plasma levels of XO activity, UA, AOPP and NO are significantly increased in BD patients compared to those of HC. Interestingly, a significant positive correlation between XO and UA was observed in BD patients. Additionally, while UA has markedly increased NO, IL-1ß, and Caspase-1 activity levels in PBMCs of BD patients, Allopurinol has exerted an immunomodulatory effect resulting in reduced NO, IL-1ß and Caspase-1 levels in PBMCs of BD patients particularly during the active stages. Collectively, our results indicate a potential clinical use of XO as a tool for assessing BD activity, and suggest that the in-vitro immunomodulatory effect of Allopurinol may have a promising therapeutic value in BD management.

Increased IL-1ß levels are associated with an imbalance of "oxidant/antioxidant" status during Behçet's disease.

Behçet's disease is a multisystem disease. It stands at the crossroad between the autoimmunity and auto-inflammatory disorders. In this study, we sought to address a relationship that might exist between interleukin-1ß (IL-1ß) and the oxidants/antioxidants markers in Behçet's patients. Behçet's disease patients (n = 78: active stage, n = 28; inactive stage, n = 50) and 41 healthy controls have been included in our study. In this context, we investigated the plasma levels of IL-1ß and the nitrosative/oxidative markers: nitric oxide (NO), advanced oxidative protein products (AOPP) and fatty acids peroxidation-malondialdehyde (MDA). The antioxidant system was assessed by measuring the plasma level of superoxide dismutase (SOD) activity. The Mann-Whitney's U and Pearson's correlation tests were used for statistical analyses. Our case-control study showed that patients in active stage displayed higher plasma levels of IL-1ß, NO, AOPP and MDA versus healthy controls and patients in inactive stage. Patients in active stage showed significantly lower SOD levels related to patients in inactive stage and healthy controls respectively, whereas patients in inactive stage showed statistically insignificant SOD level versus healthy controls. Correlation studies showed a significant positive correlation between IL-1ß and AOPP, IL-1ß and NO, and negative correlation between IL-1ß and SOD among Behçet's disease patients. In addition, we showed positive correlation between AOPP and NO, AOPP and MDA and negative correlation between NO and SOD, AOPP and SOD in Behçet's disease patients. Interestingly, our study revealed that IL-1ß levels increased and correlated with an imbalance of oxidants/antioxidants system, especially during active stage of Behçet disease. Collectively, our study indicates a possible link between IL-1ß production and nitrosative/oxidative markers during Behçet's disease. Exploiting this relationship might provide valuable outputs in the follow-up and prognosis of Behçet's disease with a potential therapeutic value.