BACKGROUND: Cancer immunotherapy has had an important role in oncologic therapeutics for patients with non-small cell lung cancer (NSCLC) using checkpoint inhibitors. We will explore the possible prognosis biomarker candidates such as: soluble OX40 (sOX40), OX40L (sOX40L), Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR), and their ligand (GITRL), 4-1BB or tumor necrosis factor receptor superfamily 9 (TNFRS9) and inducible T cell co-stimulator (ICOS) in peripheral blood of NSCLC patients.
METHODS: Fifty-eight patients were diagnosed with advanced NSCLC between January 2019 and March 2020.
RESULTS: High sOX40 and low s4-1BB levels in smokers compared non-smoker NSCLC patients. Lower sOX40L levels were found in the male than female (p < 0.05). High sOX40 and sGITRL in stage III compared to the stage IV (p < 0.05). With follow-up at 21.4 months, 44.1% and 91.1% were alive in the sGITRhigh and sGITRlow groups, respectively (p = 0.02), and 73.3% and 27.7% were alive in the sGITRLhigh and sGITRLlow groups, respectively (p = 0.02). At 22 months, 38.7% and 92.3% were alive in the sOX40Lhigh and sOX40Llow groups, respectively (p = 0.01).
CONCLUSIONS: sGITR, sGITRL, and sOX40L levels were potential prognostic biomarkers and could have an important role as new targets of immunotherapy in NSCLC patients. sGITR, sGITRL, sOX40L, and sOX40 levels were associated with smoking, sex, stage, and age in NSCLC.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies. The importance of the receptor costimulatory domain for long-term CAR-T cell engraftment and therapeutic efficacy was demonstrated with second-generation CAR-T cells. Fifth generation CAR-T cells are currently in preclinical trials. At the same time, the processes that orchestrate the activation and differentiation of CAR-T cells into a specific phenotype that predisposes them to long-term persistence are not fully understood. This review highlights ongoing research aimed at elucidating the role of CAR domains and T-cell signaling molecules involved in these processes.

Among all types of central nervous system cancers, glioma remains the most frequent primary brain tumor in adults. Despite significant advances in immunomodulatory therapies, notably immune checkpoint inhibitors, their effectiveness remains constrained due to glioma resistance. The discovery of TMIGD2 (Transmembrane and Immunoglobulin Domain Containing 2) as an immuno-stimulatory receptor, constitutively expressed on naive T cells and most natural killer (NK) cells, has emerged as an attractive immunotherapy target in a variety of cancers. The expression profile of TMIGD2 and its significance in the overall survival of glioma patients remains unknown.
In the present study, we first assessed TMIGD2 mRNA expression using the Cancer Genome Atlas (TCGA) glioma transcriptome dataset (667 patients), followed by validation with the Chinese Glioma Genome Atlas (CGGA) cohort (693 patients). Secondly, we examined TMIGD2 protein staining in a series of 25 paraffin-embedded blocks from Moroccan glioma patients. The statistical analysis was performed using GraphPad Prism 8 software.
TMIGD2 expression was found to be significantly higher in astrocytoma, IDH-1 mutations, low-grade, and young glioma patients. TMIGD2 was expressed on immune cells and, surprisingly, on tumor cells of glioma patients. Interestingly, our study demonstrated that TMIGD2 expression was negatively correlated with angiogenesis, hypoxia, G2/M checkpoint, and epithelial to mesenchymal transition signaling pathways. We also demonstrated that dendritic cells, monocytes, NK cells, gd T cells, and naive CD8 T cell infiltration correlates positively with TMIGD2 expression. On the other hand, Mantel-Cox analysis demonstrated that increased expression of TMIGD2 in human gliomas is associated with good overall survival. Cox multivariable analysis revealed that TMIGD2 is an independent predictor of a good prognosis in glioma patients.
Taken together, our results highlight the tight implication of TMIGD2 in glioma progression and show its promising therapeutic potential as a stimulatory target for immunotherapy.

Bi-specific T cell engager (BiTE), an artificial bi-functional fusion protein, has shown promising therapeutic potential in preclinical and clinical studies. However, T cells cannot be sufficiently activated by BiTE, most likely due to lacking co-stimulatory signal. We reasoned that incorporating co-stimulatory signal might have the potential to enhance the T cell activation mediated by BiTE. We, therefore, designed a chimeric fusion protein, named as CD3εζ28, which consists of the CD3ε extracellular region, the CD28 costimulatory signal and the intracellular region of CD3ζ in tandem. T cells genetically modified to express both CD3εζ28 and GFP (T-CD3εζ28-GFP) were generated by retroviral transduction. The results from in vitro experiments showed that T-CD3εζCD28-GFP cells had superior cytotoxic effects on tumor cells in presence of BiTE compared with control T cells, as evidenced by IL-2 and IFN-γ production, T cell proliferation and sequential killing assay. In vivo, T-CD3εζCD28-GFP cells showed superior anti-tumor effects in Hela-BiTE. EGFRvIII xenograft tumor model, as evaluated by tumor growth rate and T cell persistence in comparison with control T cells. In order to further confirm these findings, we generated T cells modified to express both CD3εζCD28 on cell surface and BiTE.CD19 by autocrine manner (T-CD3εζCD28-BiTE.19). The superior anti-tumor effects of T-CD3εζCD28-BiTE.19 cells could also be evidenced by the similar in vitro and in vivo experiments; thus, incorporating co-stimulatory signal may be an effective approach to improve the effector function of T cells mediated by BiTE.

Vascular endothelial cells (EC) are critical for regulation of local immune responses, through coordination of leukocyte recruitment from the blood and egress into the tissue. Growing evidence supports an additional role for endothelium in activation and costimulation of adaptive immune cells. However, this function remains somewhat controversial, and the full repertoire and durability of an enhanced endothelial costimulatory phenotype has not been wholly defined.
Human endothelium was stimulated with continuous TNFα or IFNγ for 1-48hr; or primed with TNFα or IFNγ for only 3hr, before withdrawal of stimulus for up to 45hr. Gene expression of cytokines, costimulatory molecules and antigen presentation molecules was measured by Nanostring, and publicly available datasets of EC stimulation with TNFα or IFNγ were leveraged to further corroborate the results. Cell surface protein expression was detected by flow cytometry, and secretion of cytokines was assessed by Luminex and ELISA. Key findings were confirmed in primary human endothelial cells from 4-6 different vascular beds.
TNFα triggered mostly positive immune checkpoint molecule expression on endothelium, including CD40, 4-1BB, and ICOSLG but in the context of only HLA class I and immunoproteasome subunits. IFNγ promoted a more tolerogenic phenotype of high PD-L1 and PD-L2 expression with both HLA class I and class II molecules and antigen processing genes. Both cytokines elicited secretion of IL-15 and BAFF/BLyS, with TNFα stimulated EC additionally producing IL-6, TL1A and IL-1β. Moreover, endothelium primed for a short period (3hr) with TNFα mostly failed to alter the costimulatory phenotype 24-48hr later, with only somewhat augmented expression of HLA class I. In contrast, brief exposure to IFNγ was sufficient to cause late expression of antigen presentation, cytokines and costimulatory molecules. In particular HLA class I, PD-1 ligand and cytokine expression was markedly high on endothelium two days after IFNγ was last present.
Endothelia from multiple vascular beds possess a wide range of other immune checkpoint molecules and cytokines that can shape the adaptive immune response. Our results further demonstrate that IFNγ elicits prolonged signaling that persists days after initiation and is sufficient to trigger substantial gene expression changes and immune phenotype in vascular endothelium.

Liver transplantation is an effective therapy for end-stage liver disease. However, most postoperative patients must take immunosuppressive drugs to prevent organ rejection. Interestingly, some transplant recipients have normal liver function and do not experience organ rejection after the withdrawal of immunosuppressive agents. This phenomenon, called immune tolerance, is the ultimate goal in clinical transplantation. Costimulatory molecules play important roles in T cell-mediated immune responses and the maintenance of T cell tolerance. Blocking costimulatory pathways can alter T cell responses and prolong graft survival. Better understanding of the roles of costimulatory molecules has facilitated the use of costimulatory blockade to effectively induce immune tolerance in animal transplantation models. In this article, we review the state of the art in costimulatory pathway blockade for the induction of immune tolerance in transplantation and its potential application prospects for liver transplantation.

UNASSIGNED: Programmed cell death protein-1 (PD-1) blockade therapy is one of the most remarkable immunotherapy strategies in many solid tumors, excluding glioma. The PD-1 expression, immune characteristics, and prognosis relevance in glioma remain poorly understood.
UNASSIGNED: RNA sequencing (RNA-seq) and mRNA microarray data were obtained for 325 and 301 glioma patients, respectively, from the Chinese Glioma Genome Atlas (CGGA) database. We analyzed the expression profile of PDCD1 (encoding PD-1) according to the different grade, isocitrate dehydrogenase (IDH) mutation status, and molecular subtype of glioblastoma. Gene ontology (GO) analyses were performed to explore biological processes of PD-1-related genes. Survival analysis was conducted using the Kaplan-Meier method. The findings were validated using The Cancer Genome Atlas (TCGA) RNA-seq data from 697 glioma samples. We also confirmed the PDCD1 gene expression feature and survival relevance in our own cohort of 73 glioma patients. R language was used for statistical analysis and generating figures.
UNASSIGNED: PDCD1 was enriched in glioblastoma (WHO, grade IV), IDH wild-type glioma and mesenchymal glioblastoma in CGGA and TCGA datasets; similar results were validated in our own patient cohort. GO analysis revealed that PDCD1-related genes were involved in inflammation immune responses and T cell-mediated immune responses in glioma. Circos plots indicated that PDCD1 was positively associated with CD28, ICOS, and the inhibitory checkpoint molecules CTLA4, HAVCR2, TIGIT, and LAG3. Patients with PDCD1 upregulation had much shorter overall survival.
UNASSIGNED: PDCD1 upregulation was found in more malignant phenotypes of glioma and indicated a worse prognosis. Immunotherapy of targeting PD-1 or combined with other checkpoint molecules (eg, TIM-3, LAG-3, or TIGIT) blockade may represent a promising treatment strategy for glioma.

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Tumors can avoid immune surveillance by stimulating immune inhibitory receptors that function to turn off established immune responses. By blocking the ability of tumors to stimulate inhibitory receptors on T cells, sustained, anti-tumor immune responses can be generated in animals. Thus, therapeutic blockade of immune inhibitory checkpoints provides a potential method to boost anti-tumor immunity. The CTLA-4 and PD-1Rs represent two T cell-inhibitory receptors with independent mechanisms of action. Preclinical investigations revealed that CTLA-4 enforces an activation threshold and attenuates proliferation of tumor-specific T lymphocytes. In contrast, PD-1 functions primarily as a stop signal that limits T cell effector function within a tumor. The unique mechanisms and sites of action of CTLA-4 and PD-1 suggest that although blockade of either has the potential to promote anti-tumor immune responses, combined blockade of both might offer even more potent anti-tumor activity. See related review At the Bedside: CTLA-4 and PD-1 blocking antibodies in cancer immunotherapy.