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

Heng Sheng Sow, Hreinn Benonisson, Cor Breukel, Remco Visser, Onno J. H. M. Verhagen, Arthur E. H. Bentlage, Conny Brouwers, Jill W. C. Claassens, Margot M. Linssen, Marcel Camps, Thorbald van Hall, Ferry Ossendorp, Marieke F. Fransen, Gestur Vidarsson, J. Sjef Verbeek

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Immunomodulatory antibodies blocking interactions of coinhibitory receptors to their ligands such as CTLA-4, PD1 and PD-L1 on 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 therapy revealed that an optimal therapeutic efficacy also requires binding to Fc receptors for IgG, FcγR, mediating depletion of intratumoral regulatory T cells. Here, we investigated the role of Fc binding in anti-PD-L1 antibody therapy in the MC38 C57BL/6 and CT26 BALB/c colon adenocarcinoma tumor models. In the MC38 tumor model, all IgG subclasses anti-PD-L1 showed 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-L1 mIgG2a, 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. This subclass preference 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 therapy but might play a role in some tumor models.
Original languageEnglish
Pages (from-to)345-354
JournalInternational Journal of Cancer
Volume144
Issue number2
DOIs
Publication statusPublished - 2019
Externally publishedYes

Cite this

Sow, H. S., Benonisson, H., Breukel, C., Visser, R., Verhagen, O. J. H. M., Bentlage, A. E. H., ... Verbeek, J. S. (2019). FcγR interaction is not required for effective anti-PD-L1 immunotherapy but can add additional benefit depending on the tumor model. International Journal of Cancer, 144(2), 345-354. https://doi.org/10.1002/ijc.31899