| 日時： | 令和元年6月27日（木）午後4時00分〜5時30分 |
| 場所： | 加齢研実験研究棟７階 セミナー室1 |
| 演題： | がんの抗体医薬におけるFc受容体の役割について |
| 講師： | ジェイ シェフ バービーク 客員教授 |
| 所属： | 桐蔭横浜大学生命医工学科 |
| 担当： | 遠藤 章太（所属 遺伝子導入研究分野・内線 8504） |
| 要旨： | Tumor-targeting antibodies (Abs) have limited success against solid malignancies whereas immunomodulatory Abs blocking interactions of co-inhibitory receptors to their ligands (“checkpoint blockers”) such as CTLA4 and PD-L1 on immune cells have shown impressive therapeutic efficacy. Detailed analysis of anti-CTLA4 Ab therapy revealed that optimal therapeutic efficacy requires binding to FcγR, mediating depletion of intra-tumoral Treg cells. By using a large cohort of conditional and compound FcγR KO mice combined with cell type-specific immune cell ablation we could study the role of FcγR and FcγR expressing cells in the tumor microenvironment in tumor-targeting Ab therapy in B16F10 melanoma and anti-PD-L1 Ab therapy in MC38 C57BL/6 and CT26 BALB/c colon adenocarcinoma to provide a rationale for improvement of the therapeutic efficacy of these Abs. We observed that the addition of innate stimulatory compounds, like TLR ligands, to tumor-targeting Ab therapy, greatly enhances its efficacy in solid cancers by increasing the frequency of intra-tumoral inflammatory macrophages which highly express all FcγR. All IgG subclasses of anti-PD-L1 had a strong therapeutic effect. However, in the CT26 but not the MC38 model, the anti-PD-L1 IgG2a, the IgG subclass with the highest affinity for activating FcγR, showed stronger therapeutic efficacy than other IgG subclasses. This was associated with a reduction of a myeloid cell subset with high expression of PD-L1 in the tumor microenvironment. We concluded that FcγR interaction is not required for effective anti-PD-L1 immunotherapy but can add additional benefit depending on the tumor model. |
