CTLA-4 discovery in dendritic cells – a new role in Cancer Immunotherapy?

New research suggests that dendritic cells produce and release CTLA-4, which typically inhibits anticancer responses.

Cancer immunotherapy strategies have made it increasingly evident that the immune system plays an integral role in managing and destroying cancer. Nevertheless, many mechanisms of immune suppression exist that may inhibit antitumour immunity. Recently, strategies that implement antibodies directed against negative immunologic regulators have demonstrated significant success. Cytotoxic T-lymphocyte-associate protein-4 (CTLA-4) was the first immunologic checkpoint to be clinically targeted, by the cancer immunotherapeutic ipilimumab, an FDA-approved drug to treat melanoma. After T-cell activation, CTLA-4 is upregulated on the cell surface where it functions to downregulate T cell function. Ipilimumab binds to CTLA-4 on T cells, which blocks the inhibitory signals and enhances anti-cancer immune responses.

In 2011, ipilimumab was approved by the FDA for the treatment of melanoma. What’s the dendritic cell connection? Image credit: en.wikipedia.org

In 2011, ipilimumab was approved by the FDA for the treatment of melanoma. What’s the dendritic cell connection? Image credit: en.wikipedia.org

Until now, scientists believed that CTLA-4 was expressed exclusively on CD4+ and CD8+ T cells. However, researchers at Baylor College of Medicine found that CTLA-4 is also produced and secreted by dendritic cells [1]. They compared the culture media of several matured human dendritic cell preparations with PBMC culture controls, and found that CTLA-4 was only present in the dendritic cell culture media. Although they were unable to detect CTLA-4 on dendritic cell surfaces, they confirmed intracellular expression on secretory endosomes and subsequent secretion in microvesicles. Once secreted, the microvesicles can bind to other dendritic cells, which leads to internalization and inhibition.

Interestingly, the researchers found that ablation of dendritic cell CTLA-4 expression by siRNA resulted in an upregulation CD8+ T cell proliferation and activation. In addition, they extended their in vitro findings to a mouse model of melanoma, where groups either received normal dendritic cells expressing CTLA-4 or dendritic cells treated with CTLA-4 siRNA. Mice that received the latter exhibited delayed tumor growth, decreased metastasis, and increased survival. Thus, the findings of this study suggest that inhibition of dendritic cell-secreted CTLA-4 may enhance T-cell responses and lead to better cancer immunotherapy outcomes.

At tebu-bio, we are excited to hear about new roles for dendritic cells in cancer immunotherapy strategies. We advise (and provide) dendritic cells by HemaCare for your research purposes. These monocyte derived dendritic cells are obtained from immunomagnetic separation techniques from a leukapheresis product.

Reference

[1] Halpert, M. M. et al. Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7. Stem cells and development 25, 774-787, doi:10.1089/scd.2016.0009 (2016).

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Written by Jean-François Têtu, PhD
Jean-François Têtu is Sales Manager at tebu-bio for the south of Europe and also for the UK and Eire. He also fervently defends and promotes anything from his home territory, the north of France.