Secretariat, Alumni Association, IDAC
Date Thursday, 27 June 2019, 16:00~17:30
Room 7th Floor, Seminar Room 1, IDAC Center for Basic Aging Research
Title The role of FcγR in antibody therapy in cancer
Speaker Visiting Professor J Sjef Verbeek
Affiliation Department of Biomedical Engineering, Toin University of Yokohama
Organizer Shota Endo (Dept. of Experimental Immunology・ext 8504)
Abstract 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.