Nguyen, Bao Minh Thu (2019) Blocking ‘don’t eat me’ signals CD47 and LILRB2 to enhance macrophage- and granulocyte-mediated phagocytosis of cancer cells. Bachelor, Health & Life Sciences.
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Abstract
Cancer cells can evade immune surveillance by utilizing surface receptors called immune checkpoints. CD47 and LILRB2 are two of the few receptors that can provide an inhibitory signal to immune phagocytic cells, also called ‘don’t eat me’ signals. These signals dampen the immune responses of macrophages and granulocytes by emulating the preventive signals of host cells to avoid autoimmunity. By blocking these receptors using monoclonal antibodies, the phagocytosis of cancer cells will be enhanced, thus stimulating anticancer responses by the innate immune system. As the innate immune system is the first line of defense, enhancing its activation not only helps better engulf cancer cells, but also provides long-term immunity by augmenting antigen-presentation to adaptive immune cells. Furthermore, these ‘don’t eat me’ signals can negatively affect the efficacy of rituximab (RTX), a highly effective monoclonal antibody (mAb) targeting CD20 in B cell malignancies. Synergy between anti-CD47 mAb and RTX was achieved in clinical trial for diffused large B cell lymphoma (DLBCL) patients with rituximab-resistance or refractory. Therefore, this research aims to establish the synergy between the monoclonal antibodies targeting CD47 and LILRB2 to provide a rationale for bispecific antibody production, and to achieve synergy with RTX to further increase efficacy. The anti-CD47 and anti-LILRB2 mAbs function by blocking ‘don’t eat me’ antiphagocytic signals, and rituximab mediate cell death by antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). Therefore, we determine these effects by performing the granulocyte, and macrophage phagocytosis assays on B-cell lymphoma cell lines (SUDHL6, SUDHL10, U2932), and MTS cytotoxic assay on carcinoma cell lines (DLD-1, MDA-MB231, OVCAR3). Despite varying results, the combination of anti-CD47 antibody with anti-LILRB2 antibody did synergize to enhance phagocytosis of granulocyte and macrophage compared to the single agent treatment with anti-CD47 antibody of all cell lines, except for OVCAR3. Additionally, although not uniformly the combination of anti-CD47 and anti-LILRB2 antibodies with rituximab enhanced granulocyte- and macrophage-mediated phagocytosis of cell lines U2932 and SUDHL6, respectively. Therefore, the current evidence supports the bispecific antibody production, and it is indicative that this bispecific antibody would synergy with rituximab for an enhanced treatment for B cell malignancies.
| Type: | Thesis (Bachelor) |
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| Major: | Health & Life Sciences |
| Supervisor: | Bremer, E. and Bos, N.A. |
| Datum van aanlevering: | 28 Aug 2019 |
| Last modified: | 09 Jul 2020 14:27 |
| URI: | http://ucg.studenttheses.ub.rug.nl/id/eprint/32 |
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