CRISPR Edited Knockdown of CCL5 Enhances Antitumor Immune Responses
CCL5, originally called RANTES (Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted), belongs to the CC chemokine subfamily. CCL5 expression is increased during inflammation and is produced by T cells and monocyte/macrophages participating in inflammatory responses. Like many inflammatory chemokines, CCL5 is capable of binding to and activating several chemokine receptors, specifically CCR1, CCR3, CCR4, and CCR5. Its highest affinity receptor is CCR5. While CCR5 receptor antagonists have been FDA-approved, their utilization in solid cancers has been more limited.
A recent report by Wei Yan and colleagues switched the therapeutic approach to target the ligand CCL5 and not the receptor. A novel nanoparticle-based approach was used to precisely target and edit the CCL5 gene in breast cancer. Compared to traditional therapies, this gene editing technology combined with nanoparticle-mediated treatment strategy offers a more personalized and precise treatment approach for breast cancer patients, providing a fresh avenue to enhance the effectiveness of immune therapy. Using an array of unbiased sequencing, reductionist, and preclinical models, the authors confirmed that CCL5 expression was elevated in breast cancers, being produced by tumor cells and the sparse infiltrating T cells.
When CCL5 was genetically depleted, the anti-tumor efficiency of tumor-infiltrating T cells was increased. Nanoparticles were engineered to encode CCL5-targeted CRISPR guide RNAs to specifically deplete CCL5 expression in breast cancer cells in vitro and in vivo. Mice treated with the nanoparticles demonstrated reduced tumor size and increased activation of tumor cell-responsive T cells. Overall, these data provide an exciting molecular approach using state-of-the-art nanoparticle therapy to precisely target chemokine expression and improve immune responses in vivo.
Protein Foundry has an array of high-quality recombinant chemokines for use in cell culture and preclinical studies.
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