Efficient Redirection of NK Cells by Genetic Modification with Chemokine Receptors CCR4 and CCR2B

Abstract

Natural killer (NK) cells are a subset of lymphocytes that offer great potential for cancer immunotherapy due to their natural anti-tumor activity and the possibility to safely transplant cells from healthy donors to patients in a clinical setting. However, the efficacy of cell-based immunotherapies using both T and NK cells is often limited by a poor infiltration of immune cells into solid tumors. Importantly, regulatory immune cell subsets are frequently recruited to tumor sites. In this study, we overexpressed two chemokine receptors, CCR4 and CCR2B, that are naturally found on T regulatory cells and tumor-resident monocytes, respectively, on NK cells. Using the NK cell line NK-92 as well as primary NK cells from peripheral blood, we show that genetically engineered NK cells can be efficiently redirected using chemokine receptors from different immune cell lineages and migrate towards chemokines such as CCL22 or CCL2, without impairing the natural effector functions. This approach has the potential to enhance the therapeutic effect of immunotherapies in solid tumors by directing genetically engineered donor NK cells to tumor sites. As a future therapeutic option, the natural anti-tumor activity of NK cells at the tumor sites can be increased by co-expression of chemokine receptors with chimeric antigen receptors (CAR) or T cell receptors (TCR) on NK cells can be performed in the future.

Next-Generation CEA-CAR-NK-92 Cells against Solid Tumors: Overcoming Tumor Microenvironment Challenges in Colorectal Cancer

“…This discrepancy in response profiles between the two cell lines could arise from variations in the activation of their adhesion molecules and/or actin cytoskeletons, suggesting potential differences in intracellular signaling pathways. Alternatively, the expression profile of the receptors on the surface might be too low to induce a robust migratory response, consistent with previous reports [46].…”

“…Our findings validate that the incorporated CCR4 element retained functionality despite its low membrane surface expression, likely a consequence of its position as the terminal element in the gene cassette. The response towards CCL17 and CCL22 chemokines could be further amplified by overexpressing the CCR4 receptor, as demonstrated in natural killer cells in previous studies [46]. However, this would necessitate a simpler genetic construct design, potentially omitting the PD1x component.…”

Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer

“…Along this line, we demonstrated cytotoxic function in both 2D and 3D models of triple-negative breast cancer. Further modifications, such as the inclusion of chemotaxis receptors, are expected to enhance migration and contribute to overcoming the TME [39].…”

Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation

“…Despite this progress, many limitations remain. For example, existing CAR T therapies are ineffective against solid tumors due to the immunosuppressive tumor microenvironment and low rate of tumor infiltration (Feigl et al 2023 ; Guzman et al 2023 ). Additionally, CAR T therapy can cause severe side effects, such as cytokine release syndrome and on-target, off-tumor toxicity (Chen et al 2023 ).…”