FcγR interaction is not required for effective anti‐PD‐L1 immunotherapy but can add additional benefit depending on the tumor model

Immunomodulatory antibodies blocking interactions of coinhibitory receptors to their ligands such as CTLA-4, PD1 and PD-L1on immune cells have shown impressive therapeutic efficacy in clinical studies. The therapeutic effect of these antibodies is mainly mediated by reactivating antitumor T cell immune responses. Detailed analysis of anti-CTLA4 antibody therapyrevealed that an optimal therapeutic efficacy also requires binding to Fc receptorsfor IgG, FcγR, mediating depletion of intratumoral regulatory T cells. Here, we investigated the role of Fc binding in anti- PD-L1 antibody therapyin the MC38 C57BL/6and CT26 BALB/c colon adenocarcinoma tumor models. In the MC38 tumor model, all IgG subclassesanti- PD-L1showed similar therapeutic efficacy when compared to each other in either wild-type mice or in mice deficient for all FcγR. In contrast, in the CT26 tumor model, anti- PD-L1mIgG2a, the IgG subclasswith 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-L1in the tumor microenvironment. This subclasspreference for mIgG2a was lost in C57BL/6× BALB/c F1 mice, indicating that the genetic background of the host may determine the additional clinical benefit of the high affinity antibody subclasses. Based on these data, we conclude that FcγR are not crucial for anti- PD-L1 antibody therapybut might play a role in some tumor models.