TY - JOUR
T1 - FcγR interaction is not required for effective anti-PD-L1 immunotherapy but can add additional benefit depending on the tumor model
AU - Sow, Heng Sheng
AU - Benonisson, Hreinn
AU - Breukel, Cor
AU - Visser, Remco
AU - Verhagen, Onno J. H. M.
AU - Bentlage, Arthur E. H.
AU - Brouwers, Conny
AU - Claassens, Jill W. C.
AU - Linssen, Margot M.
AU - Camps, Marcel
AU - van Hall, Thorbald
AU - Ossendorp, Ferry
AU - Fransen, Marieke F.
AU - Vidarsson, Gestur
AU - Verbeek, J. Sjef
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85056462276&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30259976
U2 - https://doi.org/10.1002/ijc.31899
DO - https://doi.org/10.1002/ijc.31899
M3 - Article
C2 - 30259976
SN - 0020-7136
VL - 144
SP - 345
EP - 354
JO - International journal of cancer
JF - International journal of cancer
IS - 2
ER -