Naïve T cells are poorly studied in cancer patients. We report that naïve T cells are prone to undergo apoptosis due to a selective loss of FAK family–interacting protein of 200 kDa (FIP200) in ovarian cancer patients and tumor-bearing mice. This results in poor antitumor immunity via autophagy deficiency, mitochondria overactivation, and high reactive oxygen species production in T cells. Mechanistically, loss of FIP200 disables the balance between proapoptotic and antiapoptotic Bcl-2 family members via enhanced argonaute 2 (Ago2) degradation, reduced Ago2 and microRNA1198-5p complex formation, less microRNA1198-5p maturation, and consequently abolished microRNA1198-5p–mediated repression on apoptotic gene Bak1. Bcl-2 overexpression and mitochondria complex I inhibition rescue T cell apoptosis and promoted tumor immunity. Tumor-derived lactate translationally inhibits FIP200 expression by down-regulating the nicotinamide adenine dinucleotide level while potentially up-regulating the inhibitory effect of adenylate-uridylate–rich elements within the 3′ untranslated region of Fip200 mRNA. Thus, tumors metabolically target naïve T cells to evade immunity.

Biodegradable magnesium (Mg) has shown great potential advantages over current bone fixation devices and vascular scaffold technologies; however, there are few reports on the immunomodulation of corrosive Mg products, the micron-sized Mg particles (MgMPs). Human monocytic leukemia cell line THP-1 was set as the in vitro cell model to estimate the immunomodulation of MgMPs on cell proliferation, apoptosis, polarization and inflammatory reaction. Our results indicated high-concentration of Mg²⁺ demoted the proliferation of the THP-1 cells and, especially, THP-1-derived macrophages, which was a potential factor that could affect cell function, but meanwhile, cell apoptosis was almost not affected by Mg²⁺. In particular, the inflammation regulatory effects of MgMPs were investigated. Macrophages exposed to Mg²⁺ exhibited down-regulated expressions of M1 subtype markers and secretions of pro-inflammatory cytokines, up-regulated expression of M2 subtype marker and secretion of anti-inflammatory cytokine. These results indicated Mg²⁺ could convert macrophages from M0 to M2 phenotype, and the bioeffects of MgMPs on human inflammatory cells were most likely due to the Mg²⁺-induced NF-κB activation reduction. Together, our results proved Mg²⁺ could be used as a new anti-inflammatory agent to suppress inflammation in clinical applications, which may provide new ideas for studying the immunomodulation of Mg-based implants on human immune system.

Significance: Aberrant PD-1 expression is known to inhibit T cell effector activity and plays a pivotal role in tumor immune escape. Since maintaining an appropriate level of PD-1 expression is of great significance, it should be highly regulated at multiple levels. Despite extensive studies to date on this topic, it remains unclear how PD-1 expression is precisely regulated at the posttranslation level both during T cell activation and among the tumor microenvironment. Here, we show that KLHL22 maintains PD-1 protein homeostasis by degrading incompletely glycosylated PD-1, thereby preventing excessive T cell suppression. KLHL22-mediated degradation of PD-1 protein will be ineffective in response to either the tumor microenvironment or treatment with 5-FU, resulting in excessive PD-1 accumulation and reduced T cell activity.

Oxidative stress is a key feature in both chronic inflammation and cancer. P38 regulated/activated protein kinase (PRAK) deficiency can cause functional disorders in neutrophils and macrophages under high oxidative stress, but the precise mechanisms by which PRAK regulates reactive oxygen species (ROS) elimination and its potential impact on CD4+ T helper subset function are unclear. The present study reveals that the PRAK-NF-E2-related factor 2(NRF2) axis is essential for maintaining the intracellular redox homeostasis of T helper 17(Th17) cells, thereby promoting Th17 cell differentiation and antitumor effects. Through mechanistic analysis, we identify NRF2 as a novel protein substrate of PRAK and find that PRAK enhances the stability of the NRF2 protein through phosphorylation NRF2 Serine(S) 558 independent of protein ubiquitination. High accumulation of cellular ROS caused by loss of PRAK disrupts both glycolysis and PKM2-dependent phosphorylation of STAT3, which subsequently impairs the differentiation of Th17 cells. As a result, Prak knockout (KO) mice display significant resistance to experimental autoimmune encephalomyelitis (EAE) but impaired antitumor immunity in a MC38 tumor model. This work reveals that the PRAK-NRF2-mediated antioxidant pathway is a metabolic checkpoint that controls Th17-cell glycolysis and differentiation. Targeting PRAK is a promising strategy for maintaining an active ROS scavenging system and may lead to potent Th17 cell antitumor immunity.

A comprehensive immunogenicity scheme is proposed to examine immune response of bovine sourced hemostasis collagen sponge to establish foundation for further researches and decrease the incidence of adverse reaction in clinical trials. Compared with negative control group without any implant, spleen and lymph nodes morphology show no apparent swelling in mice with different doses of collagen sponge implants. Immune cells population, especially lymph nodes cells population, is practically coincident with organs. However, splenic cells display slight proliferation in early phase following collagen sponge implantation. Splenic cells apoptosis also demonstrates no significant difference among all groups. T lymphocytes subsets, CD4/CD8 cells ratio, in spleen and lymph nodes are practically normal. Splenic cells Ki67 + proportions do not exhibit significant difference between collagen sponge groups and negative control group. Humoral response is determined by detection of IgG and IgM concentration in serum, not exhibiting remarkable increase with collagen sponge implantation, compared to the drastic increase in positive control group with bovine tendon implantation. Local analysis around implants by hematoxylin-eosin staining discovers slight cell infiltration around collagen sponge. Tumour necrosis factor-α immunostaining indicates slight inflammation in early phase following collagen sponge implantation, but interferon-γ immunostaining is negligible even in positive control group. Collagen sponge, especially in high dose, may have evoked benign immune response in BALB/c mice, but this response is transient. The present evaluation scheme for immune response is integrated and comprehensive, suitable for various biomaterials.

Increased serum IgE level is one of the features of allergic asthma. It is reported that IgE production can be enhanced by E-prostanoid 2 (EP2) receptor of prostaglandin E₂ (PGE₂); however, whether E-prostanoid 4 (EP4) receptor (encoded by Ptger4) has a unique or redundant role is still unclear. Here, we demonstrated the mice with B cell-specific deletion of the EP4 receptor (Ptger4^fl/fl Mb1^cre+/−) showed their serum levels of IgE were markedly increased. A much more severe airway allergic inflammation was observed in the absence of EP4 signal using the OVA-induced asthma model. Mechanistic studies demonstrated that the transcription levels of AID, GLTε, and PSTε in EP4-deficient B cells were found to be significantly increased, implying an enhanced IgE class switch. In addition, we saw higher levels of phosphorylated STAT6, a vital factor for IgE class switch. Biochemical analyses indicated that inhibitory effect of EP4 signal on IgE depended on the activation of the PI3K-AKT pathway. Further downstream, PPARγ expression was up-regulated. Independent of its activity as a transcription factor, PPARγ here primarily functioned as an E3 ubiquitin-ligase, which bound the phosphorylated STAT6 to initiate its degradation. In support of PPARγ as a key mediator downstream of the EP4 signal, PPARγ agonist induced the down-regulation of phospho-STAT6, whereas its antagonist was able to rescue the EP4-mediated inhibition of STAT6 activation and IgE production. Thus, our findings highlight a role for the PGE₂-EP4-AKT-PPARγ-STAT6 signaling in IgE response, highlighting the therapeutic potential of combined application of EP4 and PPARγ agonists in asthma.