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Anti-CD47 tri-specific killer engager enhances NK cell cytotoxicity against lung cancer
Chutipa Chiawpanit1,2,3, Yupanun Wutti-In1,4, Somsakul Pop Wongpalee5
1Cell Engineering for Cancer Therapy Research Group, Chiang Mai University, Chiang Mai, 50200, Thailand.
Abstract:
Lung cancer remains the leading cause of cancer-related deaths worldwide, with immune evasion posing a major therapeutic challenge. One key mechanism involves the 'don't eat me' signal mediated by the interaction between CD47 and signal regulatory protein alpha (SIRPα), which inhibits macrophage phagocytosis and natural killer (NK) cell cytotoxicity, facilitating tumor escape. To overcome this immune evasion, we developed a tri-specific killer engager (TriKE) targeting CD47, termed anti-CD47 TriKE, designed to enhance NK cell-mediated cytotoxicity against lung cancer cells. The activity of anti-CD47 TriKE was evaluated for its ability to induce NK cell proliferation and its binding affinity to NK cells and lung cancer cell lines (A549, NCI-H460, and NCI-H1975). At a concentration of 30 nM, anti-CD47 TriKE effectively promoted NK cell proliferation and exhibited strong binding to both NK cells and lung cancer cells. Functional assays in 2D and 3D co-culture models demonstrated that anti-CD47 TriKE significantly enhanced NK cell specificity and cytotoxicity. Notably, NK cell-mediated cytotoxicity correlated with the basal level of CD47 expression in target cells. In NCI-H1975 cells, which exhibit the highest CD47 expression, target cell viability was reduced by approximately 40%-a significantly greater reduction than in control groups. These findings highlight the potential of anti-CD47 TriKE as a promising immunotherapeutic strategy for lung cancer, particularly in targeting high-CD47-expressing tumor cells and overcoming immune evasion mechanisms.
Insights
A novel anti-CD47 TriKE immunotherapy enhances natural killer (NK) cell activity against lung cancer by blocking the "don't eat me" signal. This approach shows promise in overcoming immune evasion in high-CD47-expressing lung tumors.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Lung cancer is a leading cause of cancer mortality globally.
- Tumor immune evasion, particularly via the CD47-SIRPα axis, presents a significant therapeutic hurdle.
- The CD47
- don't eat me
- signal inhibits phagocytosis and natural killer (NK) cell cytotoxicity.
Purpose of the Study:
- To develop and evaluate a tri-specific killer engager (TriKE) targeting CD47 to enhance NK cell-mediated cytotoxicity against lung cancer.
- To assess the efficacy of anti-CD47 TriKE in promoting NK cell proliferation and binding to lung cancer cells.
- To investigate the correlation between CD47 expression and NK cell cytotoxicity in lung cancer models.
Main Methods:
- Development of anti-CD47 TriKE, a bispecific antibody construct.
- Evaluation of NK cell proliferation and binding affinity to NK cells and lung cancer cell lines (A549, NCI-H460, NCI-H1975).
- Functional assays using 2D and 3D co-culture models to assess NK cell specificity and cytotoxicity.
Main Results:
- Anti-CD47 TriKE effectively promoted NK cell proliferation and demonstrated strong binding to NK and lung cancer cells at 30 nM.
- Significant enhancement of NK cell specificity and cytotoxicity was observed in co-culture models.
- NK cell-mediated cytotoxicity strongly correlated with target cell CD47 expression, with a ~40% reduction in viability for high-CD47 NCI-H1975 cells.
Conclusions:
- Anti-CD47 TriKE is a promising immunotherapeutic agent for lung cancer.
- This strategy effectively overcomes CD47-mediated immune evasion.
- The therapy is particularly effective against lung cancer cells with high CD47 expression.
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