Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation

Kennedy, Alan; Waters, Erin; Rowshanravan, Behzad; Hinze, Claudia; Williams, Cayman; Janman, Daniel; Fox, Thomas A.; Booth, Claire; Pesenacker, Anne M.; Halliday, Neil; Soskic, Blagoje; Kaur, Satdip; Qureshi, Omar; Morris, Emma; Ikemizu, Shinji; Paluch, Christopher; Huo, Jiandong; Davis, Simon J.; Boucrot, Emmanuel; Walker, Lucy S. K.; Sansom, David M.

doi:10.1038/s41590-022-01289-w

Cited by 85 publications

(64 citation statements)

References 53 publications

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“…As expected, greater detection of CD80 uptake was observed compared to CD86 due to the higher affinity of CTLA-4 for CD80. In addition, we have observed a faster degradation of CD86, which also contributes to its more limited detection ( 37 ). Together, these data demonstrated that the universal gene editing approach could restore CTLA-4 expression and function in patient-derived T cells with three different heterozygous mutations in CTLA-4.…”

Section: Resultsmentioning

confidence: 87%

Therapeutic gene editing of T cells to correct CTLA-4 insufficiency

et al. 2022

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Heterozygous mutations in CTLA-4 result in an inborn error of immunity with an autoimmune and frequently severe clinical phenotype. Autologous T cell gene therapy may offer a cure without the immunological complications of allogeneic hematopoietic stem cell transplantation. Here, we designed a homology-directed repair (HDR) gene editing strategy that inserts the CTLA-4 cDNA into the first intron of the CTLA-4 genomic locus in primary human T cells. This resulted in regulated expression of CTLA-4 in CD4 + T cells, and functional studies demonstrated CD80 and CD86 transendocytosis. Gene editing of T cells isolated from three patients with CTLA-4 insufficiency also restored CTLA-4 protein expression and rescued transendocytosis of CD80 and CD86 in vitro. Last, gene-corrected T cells from CTLA-4 −/− mice engrafted and prevented lymphoproliferation in an in vivo murine model of CTLA-4 insufficiency. These results demonstrate the feasibility of a therapeutic approach using T cell gene therapy for CTLA-4 insufficiency.

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Section: Resultsmentioning

confidence: 87%

Therapeutic gene editing of T cells to correct CTLA-4 insufficiency

et al. 2022

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“…CD80 remain bound to CTLA-4 after transendocytosis, accompanied by the ubiquitylation of CTLA-4 and its trafficking toward late endosomes and lysosomes. In contrast, CD86 readily dissociates after internalization, which leaves CTLA-4 unmodified and permits its recycling for further ligand capture . Therefore, CD80 may be more critical to antigen presentation than CD86 because it promotes the shutdown and degradation of the immunosuppressive signaling molecule CTLA-4.…”

Section: Resultsmentioning

confidence: 99%

“…after internalization, which leaves CTLA-4 unmodified and permits its recycling for further ligand capture. 23 Therefore, CD80 may be more critical to antigen presentation than CD86 because it promotes the shutdown and degradation of the immunosuppressive signaling molecule CTLA-4.…”

Section: Resultsmentioning

confidence: 99%

Normalizing the Immune Macroenvironment via Debulking Surgery to Strengthen Tumor Nanovaccine Efficacy and Eliminate Metastasis

Chen

Yue

et al. 2022

ACS Nano

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In tumor nanovaccines, nanocarriers enhance the delivery of tumor antigens to antigen-presenting cells (APCs), thereby ensuring the robust activation of tumor antigen-specific effector T-cells to kill tumor cells. Through employment of their high immunogenicity and nanosize, we have developed a "Plug-and-Display" delivery platform on the basis of bacterial outer membrane vesicles (OMVs) for tumor nanovaccines (NanoVac), which can rapidly display different tumor antigens and efficiently eliminate lung metastases of melanoma. In this study, we first upgraded the NanoVac to increase their antigen display efficiency. However, we found that the presence of a subcutaneous xenograft seriously hampered the efficiency of NanoVac to eliminate lung metastases, with the subcutaneous xenograft mimicking the primary tumor burden in clinical practice. The primary tumor secreted significant amounts of granulocyte colony-stimulating factor (G-CSF) and altered the epigenetic features of granulocyte monocyte precursor cells (GMPs) in the bone marrow, thus disrupting systemic immunity, particularly the function of APCs, and ultimately resulting in NanoVac failure to affect metastases. These changes in the systemic immune macroenvironment were plastic, and debulking surgery of primary tumor resection reversed the dysfunction of APCs and failure of NanoVac. These results demonstrate that, in addition to the formulation design of the tumor nanovaccines themselves, the systemic immune macroenvironment incapacitated by tumor development is another key factor that cannot be ignored to affect the efficiency of tumor nanovaccines, and the combination of primary tumor resection with NanoVac is a promising radical treatment for widely metastatic tumors.

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“…The PD-1/PD-L1 pathway can form a local immunosuppressive environment [ 60 ] and play an important role in gastric cancer cell immune escape [ 61 ]. CTLA-4 mediates immunosuppression by indirectly reducing signaling through the costimulatory receptor CD28 [ 62 ]. Our results found that MAGEA11 is negatively correlated with PD-L1, PD-1, and CTLA-4, and it may be that anti-PD-1/PD-L1 has poor efficacy in the high expression group of MAGEA11 .…”

Section: Discussionmentioning

confidence: 99%

MAGEA11 as a STAD Prognostic Biomarker Associated with Immune Infiltration

et al. 2022

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Expression of MAGE family member A11 (MAGEA11) is upregulated in different tumors. However, in gastric cancer, the prognostic significance of MAGEA11 and its relationship with immune infiltration remain largely unknown. The expression of MAGEA11 in pan-cancer and the receiver operating characteristic (ROC) and survival impact of gastric cancer were evaluated by The Cancer Genome Atlas (TCGA). Whether MAGEA11 was an independent risk factor was assessed by Cox analysis. Nomograms were constructed from MAGEA11 and clinical variables. Gene functional pathway enrichment was obtained based on MAGEA11 differential analysis. The relationship between MAGEA11 and immune infiltration was determined by the Tumor Immunity Estimation Resource (TIMER) and the Tumor Immune System Interaction Database (TISIDB). Finally, MAGEA11-sensitive drugs were predicted based on the CellMiner database. The results showed that the expression of MAGEA11 mRNA in gastric cancer tissues was significantly higher than that in normal tissues. The ROC curve indicated an AUC value of 0.667. Survival analysis showed that patients with high MAGEA11 had poor prognosis (HR = 1.43, p = 0.034). In correlation analysis, MAGEA11 mRNA expression was found to be associated with tumor purity and immune invasion. Finally, drug sensitivity analysis found that the expression of MAGEA11 was correlated with seven drugs. Our study found that upregulated MAGEA11 in gastric cancer was significantly associated with lower survival and invasion by immune infiltration. It is suggested that MAGEA11 may be a potential biomarker and immunotherapy target for gastric cancer.

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Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation

Cited by 85 publications

References 53 publications

Therapeutic gene editing of T cells to correct CTLA-4 insufficiency

Therapeutic gene editing of T cells to correct CTLA-4 insufficiency

Normalizing the Immune Macroenvironment via Debulking Surgery to Strengthen Tumor Nanovaccine Efficacy and Eliminate Metastasis

MAGEA11 as a STAD Prognostic Biomarker Associated with Immune Infiltration

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