Flame retardant polypropylene (PP) composites were prepared by combining random polypropylene with uncoated and surface-treated forms of magnesium hydroxide filler and elastomeric modifiers, with and without maleic anhydride functionalization. Four types of magnesium hydroxide (MDH) with different surface treatments were compounded at amounts up to 60% by weight to PP/polyolefin elastomer (POE) matrix resin to obtain a series of composites. The tensile strength and elongation at break were measured. MDH coated with polymeric material was found to give a high elongation at break value compared with the values obtained with uncoated and vinyl silane and amino silane coated MDH. Two types of POE, i.e., neat and maleic anhydride grafted POE (POEgMA), were used to investigate the stress whitening of composites in bending deformation. POEgMA used composites showed no stress whitening while neat POE used composites showed whitening when bended.
Conventional CD4+ T cells are differentiated into CD4+CD8αα+ intraepithelial lymphocytes (IELs) in the intestine; however, the roles of intestinal epithelial cells (IECs) are poorly understood. Here, we showed that IECs expressed MHC class II (MHC II) and programmed death–ligand 1 (PD-L1) induced by the microbiota and IFN-γ in the distal part of the small intestine, where CD4+ T cells were transformed into CD4+CD8αα+ IELs. Therefore, IEC-specific deletion of MHC II and PD-L1 hindered the development of CD4+CD8αα+ IELs. Intracellularly, PD-1 signals supported the acquisition of CD8αα by down-regulating the CD4-lineage transcription factor, T helper–inducing POZ/Krüppel-like factor (ThPOK), via the Src homology 2 domain–containing tyrosine phosphatase (SHP) pathway. Our results demonstrate that noncanonical antigen presentation with cosignals from IECs constitutes niche adaptation signals to develop tissue-resident CD4+CD8αα+ IELs.
Clinical trials have demonstrated that an increased number of effector cells, especially tumor-specific T cells, is positively linked with patients’ prognosis. Although the discovery of checkpoint inhibitors (CPIs) has led to encouraging progress in cancer immunotherapy, the lack of either T cells or targets for CPIs is a limitation for patients with poor prognosis. Since interleukin (IL)-2 and IL-7 are cytokines that target many aspects of T-cell responses, they have been used to treat cancers. In this review, we focus on the basic biology of how these cytokines regulate T-cell response and on the clinical trials using the cytokines against cancer. Further, we introduce several recent studies that aim to improve cytokines’ biological activities and find the strategy for combination with other therapeutics.
The emergence of a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has become a significant health concern worldwide. Undoubtedly, a better understanding of the innate and adaptive immune responses against SARS-CoV-2 and its relationship with the coronavirus disease 2019 (COVID-19) pathogenesis will be the sole basis for developing and applying therapeutics. This review will summarize the published results that relate to innate immune responses against infections with human coronaviruses including SARS-CoV-1 and SARS-CoV-2 in both humans and animal models. The topics encompass the innate immune sensing of the virus to the dysregulation of various innate immune cells during infection and disease progression.
BackgroundrhIL-7-hyFc is a hybrid Fc-fused recombinant human interleukin-7 (NT-I7; efineptakin-alfa) with enhanced bioactivity. In a previous study, we found that a systemic administration of rhIL-7-hyFc induced antitumor effect by increasing CD8+ T cells in the tumor microenvironment. rhIL-7-hyFc monotherapy increased not only PD-1+ tumor-reactive but also intratumoral PD-1- bystander CD8+ T cells. Therefore, we hypothesized that the activation of PD-1- bystander T cells in tumors would enhance the antitumor activity of rhIL-7-hyFc. Here we evaluated the antitumor effect of combination therapy with rhIL-7-hyFc and a bispecific antibody (bsAb), anti-PD-L1xCD3ε, targeting both a tumor-associated antigen (PD-L1) and a T-cell stimulatory antigen (CD3ε).MethodsIn vitro cell culture. For analysis of T cell activation and cytotoxicity, splenocytes were isolated from PD-L1 knock-out (KO) mice and co-cultured with either wild type (MC-38WT) and PD-L1-depleted (MC-38ΔPD-L1) tumor cells in the presence of bsAb for 48 hours. In vivo treatment. Tumor-bearing mice were treated subcutaneously (s.c.) with 1.25 mg/kg of rhIL-7-hyFc. An indicated dose of bsAb was daily treated intravenous (i.v.) or intratumoral (i.t.) route starting from 3 days after the rhIL-7-hyFc treatment for a total 5 times.Preparation of tumor-infiltrating cells. Tumor tissues were harvested after 7 days of rhIL-7-hyFc treatment. Single-cell suspensions were prepared through mechanical separation followed by collagenase D and DNAse I treatment.ResultsAnti-PD-L1xCD3ε bsAb induced the PD-L1-specific activation and cytotoxicity of CD8+ T cells in vitro (figure 1).rhIL-7-hyFc combined with a systemic administration of bsAb enhanced antitumor responses, although loss of body-weight was shown with high-dose bsAb combination (figure 2)The combination of rhIL-7-hyFc with a systemic administration of bsAb increased not only the frequency of CD8+ T cells in tumors but also the PD-1- bystander CD8+ T cells with enhanced expression of a Granzyme B (figure 3).Intratumoral administration of high-dose bsAb enhanced antitumor response of rhIL-7-hyFc without body-weight loss (figure 4).Abstract 450 Figure 1MC-38WT and MC-38ΔPD-L1tumor cells were cultured in vitro. (a) PD-L1 expression levels on each cell line. (b) Splenocytes isolated from PD-L1 KO mice were co-cultured with indicated tumor cells (E:T = 20:1) in the presence of bsAb. Expression levels of activation markers, such as CD69 and CD25, on the CD8+ T cells were analyzed by flow cytometry. (c) Cytotoxicity against tumors was analyzed in the presence of bsAb. Cytotoxicity was calculated using the formula: [1 - live target cells(sample)/live target cells(control)] × 100Abstract 450 Figure 2(a-b) Mice bearing MC-38 tumors were treated with different doses of bsAb (i.v.) as indicated in (a) (n = 5 per group). (b) Shown are mean tumor growth curves (left) and body-weight changes (right). (c-d) Mice bearing MC-38 tumors were treated either 1.25 mg/kg of rhIL-7-hyFc (s.c.), indicated doses of bsAb (i.v.), or combination of each therapy as indicated in (c). In the case of combination therapy with 1 ug bsAb, mice were treated only for the first 3 doses of bsAb because of body-weight loss (n = 5–7 per group). (d) Shown are mean tumor growth curves (left) and body-weight changes (right). Arrows indicate the dosing of bsAb. Data are represented as mean ± SEM. Statistical significance was analyzed by two-way ANOVA with bonferroni’s multiple comparisons for (b and d). *P<0.05;**P<0.01;***P<0.001Abstract 450 Figure 3(a) Experimental scheme for the analysis of tumor-infiltrating T cells (n = 4 per group). (b) Frequencies of CD8+, CD4+Foxp3- T helper (Th), and CD4+Foxp3+ T regulatory (Treg) cells among CD45+ cells. (c) Frequencies of CD4+Foxp3+ Treg cells among CD4+ T cells. (d) The ratio of CD8+ T cells to Treg cells. (e) Frequencies of PD-1- cells among CD8+ T cells. (f) Frequencies of Granzyme B (GzmB) expressing cells among PD-1+ or PD-1- CD8+ T cells. Data are represented as mean ± SD. Statistical significance was analyzed by one-way ANOVA with bonferroni’s multiple comparisons. *P<0.05;**P<0.01;***P<0.001Abstract 450 Figure 4(a-b) Mice bearing MC-38 tumors were treated i.t. with bsAb as indicated in (a) (n = 6–7 per group). (b) Shown are mean tumor growth curves (left) and body-weight changes (right). (c-d) Mice bearing MC-38 tumors were treated either 1.25 mg/kg of rhIL-7-hyFc (s.c.), indicated doses of BsAb (i.t.), or combination of each therapy as indicated in (c). (n = 9–10 per group). (d) Shown are mean tumor growth curves (left) and body-weight changes (right). Arrows indicate the dosing of bsAb. Data are represented as mean ± SEM. Statistical significance was analyzed by two-way ANOVA with bonferroni’s multiple comparisons for tumor growth graphs. *P<0.05;**P<0.01;***P<0.001ConclusionsThe combination treatment of anti-PD-L1xCD3ε bsAb with rhIL-7-hyFc enhances antitumor efficacy.Both systemic and intratumoral administration of bsAb with rhIL-7-hyFc augments antitumor effects, and intratumoral administration induced less weight loss than systemic administration.The activation of PD-1- bystander CD8+ T cells in tumors by the combination of bsAb and rhIL-7-hyFc suggests that antitumor response may be partially mediated by the targeted activation of bystander CD8+ T cells. Our results serve as a proof-of-concept that the combination of rhIL-7-hyFc, a strong T cell amplifier, with bsAb, a tumor-targeted T-cell stimulator, would be a promising strategy for cancer immunotherapy.AcknowledgementsThis research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT)(NRF-2020M3H1A1075314) and the grants from Research Institute of NeoImmuneTech, Inc.Ethics ApprovalThis study was approved by POSTECH institutional animal care and use committee; approval number POSTECH-2020-0057.
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