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PD-1 blockade augments anti-neuroblastoma immune response induced by $anti-GD_{2}$ antibody ch14.18/CHO
| Content Provider | Scilit |
|---|---|
| Author | Siebert, Nikolai Zumpe, Maxi Jüttner, Madlen Troschke-Meurer, Sascha Lode, Holger N. |
| Copyright Year | 2017 |
| Description | Journal: OncoImmunology Immunotherapy with $anti-GD_{2}$ antibody (Ab) ch14.18/CHO is effective for treatment of high-risk neuroblastoma (NB) patients and is mainly based on $GD_{2}$-specific Ab-dependent cellular cytotoxicity (ADCC). Strategies to further enhance the efficacy are important and currently explored in prospective clinical trials randomizing ch14.18/CHO ± IL-2. Recently, expression of programmed death 1 (PD-1) inhibitory receptor by effector cells and its ligand (PD-L1) by tumor cells has been shown. Here, we report for the first time effects of PD-1 blockade on ch14.18/CHO-based immunotherapy and mechanisms involved. Expression of PD-1 and PD-L1 on NB and effector cells was analyzed by RT-PCR and flow cytometry in the presence of ch14.18/CHO and/or IL-2. The effect of PD-1 blockade on ch14.18/CHO-mediated anti-NB immune response was evaluated using anti-PD-1 Ab both in vitro (Nivolumab) and in a syngeneic PD-L1^{+}/GD_{2}$^{+}$ NB mouse model (anti-mouse PD-1). Culture of NB cells LA-N-1 (low PD-L1 baseline expression) with leukocytes and subtherapeutic ch14.18/CHO concentrations for 24 h induced strong upregulation of PD-L1, which was further increased by IL-2 resulting in complete inhibition of ch14.18/CHO-mediated ADCC. Importantly, blockade with Nivolumab reversed the PD-L1-dependent inhibition of ADCC. Similarly, co-incubation with anti-CD11b Ab abrogated the PD-L1 upregulation and restored ADCC. Mice treated with ch14.18/CHO in combination with PD-1 blockade showed a strong reduction of tumor growth, prolonged survival and the highest cytotoxicity against NB cells. In conclusion, ch14.18/CHO-mediated effects upregulate the inhibitory immune checkpoint PD-1/PD-L1, and combination of ch14.18/CHO with PD-1 blockade results in synergistic treatment effects in mice representing a new effective treatment strategy against $GD_{2}$-positive cancers. |
| Related Links | https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1343775?needAccess=true https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665083/pdf |
| e-ISSN | 2162402X |
| DOI | 10.1080/2162402x.2017.1343775 |
| Journal | OncoImmunology |
| Issue Number | 10 |
| Volume Number | 6 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2017-07-05 |
| Access Restriction | Open |
| Subject Keyword | Journal: OncoImmunology Immune Checkpoint Blockade Neuroblastoma Programmed Cell Death 1 (pd-1) Ligand |
| Content Type | Text |
