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Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long-term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell-intrinsic CD96 enhances the chemotherapeutic response in a patient-derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid β-oxidation via the CD155-CD96-Src-Stat3-Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell-intrinsic CD96 and an attractive target in improving the chemotherapeutic response. [ABSTRACT FROM AUTHOR]

CD96 was identified as a novel immune checkpoint. However, the role of CD96 in the gastric cancer (GC) microenvironment remains fragmentary. This study aimed to probe the clinical significance of CD96 to predict prognosis and therapeutic responsiveness, and to reveal the immune contexture and genomic features correlated to CD96 in GC patients. We enrolled 496 tumor microarray specimens of GC patients from Zhongshan Hospital (ZSHS) for immunohistochemical analyses. Four hundred and twelve GC patients from the Cancer Genome Atlas (TCGA) and 61 GC patients treated with pembrolizumab from ERP107734 published in the European Nucleotide Archive (ENA) were gathered for further analysis of the association between CD96+ cell infiltration and immune contexture, molecular characteristics, and genomic features by CIBERSORT and gene set enrichment analysis. Clinical outcomes were analyzed by Kaplan–Meier curves, the Cox model, interaction testing, and receiver operating characteristic analysis. High CD96+ cell infiltration predicted poor prognosis and inferior survival benefits from fluorouracil‐based adjuvant chemotherapy in the ZSHS cohort whereas superior therapeutic responsiveness to pembrolizumab was shown in the ENA cohort. CD96‐enriched tumors showed an immunosuppressive tumor microenvironment featured by exhausted CD8+ T‐cell infiltration in both the ZSHS and TCGA cohorts. Moreover, in silico analysis for the TCGA cohort revealed that several biomarker‐targeted pathways displayed significantly elevated enrichment levels in the CD96 high subgroup. This study elucidated that CD96 might drive an immunosuppressive contexture with CD8+ T‐cell exhaustion and represent an independent adverse prognosticator in GC. CD96 could potentially be a novel biomarker for precision medicine of adjuvant chemotherapy, immunotherapy, and targeted therapies in GC. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are regarded as the host's first line of defense against viral infection. Moreover, the involvement of NK cells in chronic obstructive pulmonary disease (COPD) has been documented. However, the specific mechanism and biological changes of NK cells in COPD development have not been determined. In this study, we extracted NK cells from the peripheral blood of 18 COPD patients who were recovering from an acute exacerbation and 45 healthy donors (HDs), then we labeled NK cells with different antibodies and analyzed with flow cytometry. The data showed that the frequencies of total NK cells in the peripheral blood of COPD patients were lower compared with HDs. Moreover, the inhibitory receptors on NK cells expressed higher levels and the expression of activating receptors were generally low. Importantly, both the expression levels of CD96 in NK cells and the frequencies of CD96+ NK cells were significantly upregulated in COPD patients. These findings suggest that surface receptor CD96 from NK cells may be a risk factor in the evolution of COPD. [ABSTRACT FROM AUTHOR]

Keywords: acute megakaryoblastic leukemia; Down syndrome; CLEC12A; TIM3; CD96 EN acute megakaryoblastic leukemia Down syndrome CLEC12A TIM3 CD96 e7 e11 5 12/21/20 20210101 NES 210101 Acute myeloid leukaemia (AML) is a genetically and clinically heterogeneous disease, characterized by expansion of undifferentiated myeloid precursor cells.1 Despite an increased understanding of the biology and therapeutic advances, the outcomes of AML patients remain unsatisfactory. The average CLEC12A-positive cell rate was significantly lower in FAB-M7 cases (10-8%) than that in non-FAB-M7 cases (91-8%, I P i = 2.8E-20; Fig 1C); however, the average TIM3-positive cell rate did not differ significantly between the two groups (67-5% vs. 62-1%, respectively, I P i = 0-66). The average CD96-positive cell rate was also significantly lower in samples from FAB-M7 patients (20-7%) than in those from non-FAB-M7 patients (59-5%, I P i = 0-0002). [Extracted from the article]

CD96 is a member of the poliovirus receptor (PVR, CD155)‐nectin family that includes T cell Ig and ITIM domain (TIGIT) and CD226. While CD96, TIGIT, and CD226 have important roles in regulating NK cell activity, and TIGIT and CD226 have also been shown to regulate T cell responses, it is unclear whether CD96 has inhibitory or stimulatory function in CD8+ T cells. Here, we demonstrate that CD96 has co‐stimulatory function on CD8+ T cells. Crosslinking of CD96 on human or mouse CD8+ T cells induced activation, effector cytokine production, and proliferation. CD96 was found to transduce its activating signal through the MEK‐ERK pathway. CD96‐mediated signaling led to increased frequencies of NUR77‐ and T‐bet‐expressing CD8+ T cells and enhanced cytotoxic effector activity, indicating that CD96 can modulate effector T cell differentiation. Antibody blockade of CD96 or genetic ablation of CD96 expression on CD8+ T cells impaired expression of transcription factors and proinflammatory cytokines associated with CD8+ T cell activation in in vivo models. Taken together, CD96 has a co‐stimulatory role in CD8+ T cell activation and effector function. [ABSTRACT FROM AUTHOR]

CD96 has recently been shown to be a potent immune checkpoint molecule in mice, but a similar role in humans is not known. In this study, we provide a detailed map of CD96 expression across human lymphocyte lineages, the kinetics of CD96 regulation on T‐cell activation and co‐expression with other conventional and emerging immune checkpoint molecules. We show that CD96 is predominantly expressed by T cells and has a unique lymphocyte expression profile. CD96high T cells exhibited distinct effector functions on activation. Of note, CD96 expression was highly correlated with T‐cell markers in primary and metastatic human tumors and was elevated on antigen‐experienced T cells and tumor‐infiltrating lymphocytes. Collectively, these data demonstrate that CD96 may be a promising immune checkpoint to enhance T‐cell function against human cancer and infectious disease. CD96 has recently been shown to be a potent immune checkpoint molecule in mice, but a similar role in humans is not known. In this study, we show that CD96 is predominantly expressed by T cells and has a unique lymphocyte expression profile. CD96 expression was elevated on antigen‐experienced T cells and tumor‐infiltrating lymphocytes. [ABSTRACT FROM AUTHOR]

CD155 is the fifth member in the nectin-like molecule family, and functions as the receptor of poliovirus; therefore, CD155 is also referred to as necl-5, or PVR. As an immunoglobulin-like adhesion molecule, CD155 is involved in cell motility, and natural killer and T cell-mediated immunity. CD155 is barely or weakly expressed in various normal human tissues, but frequently overexpressed in human malignant tumors. CD155 overexpression promotes tumor cell invasion and migration, and is associated with tumor progression and poor prognosis. As the ligand for both costimulatory receptor CD226 and coinhibitory receptor TIGIT and CD96 on natural killer and T cells, CD155 seems to play a dual role in oncoimmunity. However, some recent studies indicate that CD155 overexpression may induce tumor immune escape. Taken together, CD155 may be considered as a target for the treatment of tumors with CD155 overexpression. [ABSTRACT FROM AUTHOR]

While therapies targeting the co-inhibitory or immune checkpoint receptors PD-1 and CTLA-4 have shown remarkable success in many cancers, not all patients benefit from these therapies. This has catalyzed enormous interest in the targeting of other immune checkpoint receptors. In this regard, TIGIT and CD96 have recently entered the limelight as novel immune checkpoint receptor targets. TIGIT and CD96 together with the co-stimulatory receptor CD226 form a pathway that is analogous to the CD28/ CTLA-4 pathway, in which shared ligands and differential receptor:ligand affinities fine-tune the immune response. Although the roles of TIGIT and CD96 as immune checkpoint receptors in T cell and natural killer cell biology are just beginning to be uncovered, accumulating data support the targeting of these receptors for improving anti-tumor immune responses. A clear understanding of the immune cell populations regulated by TIGIT and CD96 is key to the design of immunotherapies that target these receptors in combination with other existing immune checkpoint blockade therapies. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia is often called as stem cell disease that presents with treatment failure and poor disease outcome. Leukemic stem cells in acute myeloid leukemia ( AML) are enriched in Lineage-/ CD38−/ CD34+ compartment of CD34−positive AML. Many markers important for stem cell biology have been reported for their association with leukemic stem cell population, but what remains clinically most important is a rapid identification of prognostic information. In this study, we evaluated four signal transduction pathways and thirteen markers on Lin−/ CD38−/ CD34+ population in AML. Expressions were compared in different AML subtypes, survival, and treatment outcome groups. We observed that markers important in homing, cell quiescence, and signal propagation such as CD44, CD96, CD90, WT-1, CD123 and CD25 were most significantly differentially expressed on Lin-/ CD38−/ CD34+ population in AML from their normal counterparts ( P < 0.05, Mann-Whitney). Constitutive activation of phospho ERK, AKT, and STAT5 in these cells was associated with poor outcome. Also, an increased frequency of putative leukemic stem cell population shows negative impact on treatment outcome and overall survival, suggesting that initial evaluation of AML samples for pLSC frequency and constitutively activated signaling pathway can provide prognostic and therapeutic information at the time of diagnosis. [ABSTRACT FROM AUTHOR]

Opitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed withOTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes inCD96 or ASXL1.However, the cohort is too small to make generalizations about the genetic etiology of these diseases. [ABSTRACT FROM AUTHOR]