Cd8 T Cells
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2021 ◽  
Vol 4 (1) ◽  
Agnese Losurdo ◽  
Caterina Scirgolea ◽  
Giorgia Alvisi ◽  
Jolanda Brummelman ◽  
Valentina Errico ◽  

Gut ◽  
2021 ◽  
pp. gutjnl-2021-324170
Ningning Liu ◽  
Xiaomei Wang ◽  
Clifford John Steer ◽  
Guisheng Song

ObjectiveKupffer cells (KCs) protect against hepatocellular carcinoma (HCC) by communicating with other immune cells. However, the underlying mechanism(s) of this process is incompletely understood.DesignFVB/NJ mice were hydrodynamically injected with AKT/Ras and Sleeping Beauty transposon to induce HCC. Mini-circle and Sleeping Beauty were used to overexpress microRNA-206 in KCs of mice. Flow cytometry and immunostaining were used to evaluate the change in the immune system.ResultsHydrodynamic injection of AKT/Ras into mice drove M2 polarisation of KCs and depletion of cytotoxic T cells (CTLs) and promoted HCC development. M1-to-M2 transition of KCs impaired microRNA-206 biogenesis. By targeting Klf4 (kruppel like factor 4) and, thereby, enhancing the production of M1 markers including C-C motif chemokine ligand 2 (CCL2), microRNA-206 promoted M1 polarisation of macrophages. Indeed, microRNA-206-mediated increase of CCL2 facilitated hepatic recruitment of CTLs via CCR2. Disrupting each component of the KLF4/CCL2/CCR2 axis impaired the ability of microRNA-206 to drive M1 polarisation of macrophages and recruit CTLs. In AKT/Ras mice, KC-specific expression of microRNA-206 drove M1 polarisation of KCs and hepatic recruitment of CTLs and fully prevented HCC, while 100% of control mice died from HCC. Disrupting the interaction between microRNA-206 and Klf4 in KCs and depletion of CD8+ T cells impaired the ability of miR-206 to prevent HCC.ConclusionsM2 polarisation of KCs is a major contributor of HCC in AKT/Ras mice. MicroRNA-206, by driving M1 polarisation of KCs, promoted the recruitment of CD8+ T cells and prevented HCC, suggesting its potential use as an immunotherapeutic approach.

2021 ◽  
Claudia Urueña ◽  
Paola Lasso ◽  
David Bernal-Estevez ◽  
Diego Rubio ◽  
Ana Janeth Salazar ◽  

Abstract Neoadjuvant chemotherapy (NAT) in breast cancer (BC) has been used to reduce tumor burden prior to surgery. However, the impact on prognosis depends on the establishment of Pathological Complete Response (pCR), which is influenced by tumor-infiltrating lymphocyte levels and the activation of the antitumor immune response. Nonetheless, NAT can affect immune infiltration and the quality of the response. Here, we showed that NAT induces dynamic changes in the tumor microenvironment (TME). After NAT, an increase of regulatory T cells and a decrease of CD8 + T cells was found in tumor, correlated with the presence of metastatic cells in lymph nodes. In addition, an increase of polymorphonuclear myeloid-derived suppressor like cells was found in luminal patients post-NAT. pCR patients showed a balance between the immune populations, while non-pCR patients presented an inverse relationship in the frequency of CD68 + versus CD3 + , CD8 + , and CD20 + cells. Moreover, activated T cells were found in peripheral blood, as well as an increase in T cell clonality with a lower diversity post-NAT. Overall, these results shown that NAT induces an activation of immune response, however, a balance in the TME seems to be related to a better antigenic presentation and therefore a better response to treatment.

2021 ◽  
Vol 27 ◽  
Hongmei Zheng ◽  
Yue Ning ◽  
Yang Yang ◽  
Yuting Zhan ◽  
Haihua Wang ◽  

Aims: β-catenin is a critical regulating factor of the Wnt pathway, which is closely linked to tumorigenesis, tumor growth, metastasis, and tumor immunity. Our study focused on exploring the relationship between β-catenin and clinicopathological features, prognosis, as well as infiltrating immune cells and immune scores, so as to illustrate its clinical significance in NSCLC.Materials and Methods: The β-catenin mRNA (CTNNB1) and protein expression data were downloaded from the UALCAN and the UCSC Xena website, respectively. All tumor-immune infiltrating cells’ data were downloaded from the TIMER platform and immune scores were downloaded from ESTIMATE website. The expression of β-catenin protein in our cohort was measured by immunohistochemistry.Results: β-catenin mRNA level was higher in lung adenocarcinoma (LUAD) compared to normal tissues (p < 0.001) and was related to overall survival (OS) (p < 0.001) and post-progression survival (PPS) (both p = 0.049) in LUAD. Aberrant β-catenin protein expression was higher in male and lung squamous cell carcinoma (LUSC) patients (both p = 0.001). Also, it was considered to be a prognosis factor independently (p = 0.034). In addition, β-catenin protein was negatively correlated with CD8+T cells (r = −0.128, p = 0.008), neutrophils (r = −0.198, p < 0.001), immune score (r = −0.109, p = 0.024), stromal score (r = −0.097, p = 0.045), and ESTIMATE score (r = −0.113, p = 0.020).Conclusions: Aberrant β-catenin protein expression was evidently higher in NSCLC and might serve as a biomarker for poor prognosis. Most importantly, β-catenin protein might play an important part in tumor immunity and the tumor microenvironment by inhibiting the infiltration of CD8+ T cells and neutrophils.

2021 ◽  
Avinash Sahu ◽  
Xiaoman Wang ◽  
Phillip Munson ◽  
Jan Klomp ◽  
Xiaoqing Wang ◽  

Drugs that kill tumors through multiple mechanisms have potential for broad clinical benefits, with a reduced propensity to resistance. We developed BipotentR, a computational approach to find cancer-cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway. Using tumor metabolism as proof-of-principle, BipotentR identified 38 candidate immune-metabolic regulators by combining epigenomes with bulk and single-cell tumor transcriptomes from patients. Inhibition of top candidate ESRRA (Estrogen Related Receptor Alpha) killed tumors by direct effects on energy metabolism and two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization (ii) antigen-presentation stimulation, recruiting CD8+T cells into tumors. ESRRA is activated in immune-suppressive and immunotherapy-resistant tumors of many types, suggesting broad clinical relevance. We also applied BipotentR to angiogenesis and growth-suppressor pathways, demonstrating a widely applicable approach to identify drug targets that act simultaneously through multiple mechanisms. BipotentR is publicly available at

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Heng Zhang ◽  
Qiang Ju ◽  
Jing Ji ◽  
Yanjie Zhao

Fumarate hydratase (FH) is an important enzymatic component in the tricarboxylic acid cycle. Studies have reported that FH plays an important role in hereditary leiomyomatosis and renal cell cancer (HLRCC). However, the role of FH in human different cancers remains unknown. This study is aimed at analyzing the prognostic value of FH and demonstrating the correlation between FH expression and tumor immunity. Results showed that FH was mutated or copy number varied in 27 types of cancer. FH mRNA was abnormally upregulated across various cancers. Survival analysis suggested high expression of FH was associated with poor prognosis in many cancer types, including lung adenocarcinoma (LUAD). Additionally, FH expression was associated with immune infiltration, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, especially in liver hepatocellular carcinoma (LIHC), LUAD, and lung squamous cell carcinoma (LUSC). Moreover, FH expression showed a strong correlation with immune checkpoint markers in LUAD and testicular germ cell tumors (TGCT). These results indicate that FH is an immunotherapeutic target and a potential prognostic biomarker in LUAD.

2021 ◽  
Vol 233 (5) ◽  
pp. S244-S245
Eihab N. Abdelfatah ◽  
Toshifumi Hoki ◽  
Takaaki Oba ◽  
Hongbin N. Chen ◽  
Kristopher Attwood ◽  

2021 ◽  
Leonardo Estrada ◽  
Didem Agac Cobanoglu ◽  
Aaron Wise ◽  
Robert Maples ◽  
Murat Can Cobanoglu ◽  

Viral infections drive the expansion and differentiation of responding CD8+ T cells into variegated populations of cytolytic effector and memory cells. While pro-inflammatory cytokines and cell surface immune receptors play a key role in guiding T cell responses to infection, T cells are also markedly influenced by neurotransmitters. Norepinephrine is a key sympathetic neurotransmitter, which acts to suppress CD8 + T cell cytokine secretion and lytic activity by signaling through the beta2-adrenergic receptor (ADRB2). Although ADRB2 signaling is considered generally immunosuppressive, its role in regulating differentiation of effector T cells in response to infection has not been investigated. Using an adoptive transfer approach, we compared the expansion and differentiation of wild type (WT) to Adrb2-/- CD8 + T cells throughout the primary response to vesicular stomatitis virus (VSV) infection in vivo. We measured the dynamic changes in transcriptome profiles of antigen-specific CD8 + T cells as they responded to VSV. Within the first 7 days of infection, WT cells out-paced the expansion of Adrb2-/- cells, which correlated with reduced expression of IL-2 and the IL-2Ralpha; in the absence of ADRB2. RNASeq analysis identified over 300 differentially expressed genes that were both temporally regulated following infection and selectively regulated in WT vs Adrb2-/- cells. These genes contributed to major transcriptional pathways including cytokine receptor activation, signaling in cancer, immune deficiency, and neurotransmitter pathways. By parsing genes within groups that were either induced or repressed over time in response to infection, we identified three main branches of genes that were differentially regulated by the ADRB2. These gene sets were predicted to be regulated by specific transcription factors involved in effector T cell development, such as Tbx21 and Eomes. Collectively, these data demonstrate a significant role for ADRB2 signaling in regulating key transcriptional pathways during CD8 + T cells responses to infection that may dramatically impact their functional capabilities and downstream memory cell development.

2021 ◽  
Francesca Simoncello ◽  
Giulia Maria Piperno ◽  
Nicoletta Caronni ◽  
Tiziana Battini ◽  
Ambra Cappelletto ◽  

Background: Tumor infiltrating neutrophils generally correlates to worst prognosis and refractoriness to immunotherapy yet the complexity and significance of diverse subsets resident in tumor tissues has just begun to emerge. In lung tumors, a network of neutrophils states with graded protumorigenic properties is conserved between mouse and humans and include a subset of mature, long lived cells expressing the sialic-acid-binding protein SiglecF (SiglecFhigh neu). The mechanism of recruitment of SiglecFhigh neu into tumor tissues and the impact on local anti-tumor T cell responses and interference with immunotherapy is still elusive. Methods: We used an immunogenic model of KrasG12D Tp53 null adenocarcinoma of the lung to screen for factors inducing the recruitment of SiglecFhigh neu, followed by gene editing to delete selected candidates. We analyzed frequencies and effector functions of endogenous CD8 T cell responses in controls and SiglecFhigh neu depleted tumors by flow cytometry and functional assays. Tissues fluorescence and confocal imaging of lung sections was used to explore the relative distribution of neu and CD8 T cells. To establish the impact of SiglecFhigh neu on anti-tumoral immune responses we treated cohort of animals with anti-PD-L1 antibodies to evaluate tumor growth in control conditions and under therapy. Results: We found that tumor tissues express high levels of CXCL5, mapping to cancer cells. Upon deletion of chemokine expression by gene editing, the recruitment of SiglecFhigh neu was almost entirely abrogated. In tumors depleted of SiglecFhigh neu, the density of tumor specific endogenous CD8 T cells was 3-fold higher than in controls and showed significantly enhanced activation and effector functions. Importantly, checkpoint blockade with anti PD-L1 antibodies was ineffective in control tumors but showed a significant benefit in SiglecFhigh neu depleted tumors. Conclusion: This study demonstrates that SiglecFhigh neu differentiating in lung tumor tissues inhibit local CD8 T cell responses and interfere with the success of checkpoint blockade. These data suggest that blocking selectively tissue resident neu may promote better responses to immunotherapy.

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