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

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.

Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models

“…The MC38 colon adenocarcinoma syngeneic model on a C57BL/6 background is highly immunogenic and it has been demonstrated to be sensitive to anti-PD-L1 immune checkpoint monotherapy [41,42]. To test if LY364947 boosts the antitumor effect of anti-PD-L1 mAb, we examined the anti-tumor effect of these treatments on subcutaneously growing MC38 tumors in immune-competent C57BL/6 mice.…”

Isotype selection for antibody-based cancer therapy

“…However, although another study confirmed that Fc-mediated depletion of myeloid cells in the TME contributes to the therapeutic effect of anti-PD-L1 antibodies, this effect was found to be dependent on the mouse genetic background as it occurred in CT26 tumours transplanted in BALB/c but not MC38 tumours in C57BL/6 mice 69 . The depleted myeloid cell subset was the one with the highest PD-L1 expression whereas PD-L1 expression on the tumour cells did not contribute to the therapeutic effect of anti-PD-L1 antibody 69 . Currently, there are three clinically approved anti-PD-L1 mAbs, two of which have a mutated Fc tail with abrogated FcγR binding (atezolizumab, durvalumab) and one is a wild-type IgG1 (avelumab).…”

“…These checkpoint proteins are expressed on activated T cells and limit excessive T cell responses. As a means of immune resistance, the ligands of PD-1 are often expressed by tumour cells 67 as well as by myeloid cells infiltrating the TME 68,69 . Checkpoint blockade leads to enhanced T cell activation 67,70 and, consequently, the clinical introduction of checkpoint inhibitors led to a tremendous improvement of cancer therapy for several different types of cancers.…”

Identification of a neo-epitope dominating endogenous CD8 T cell responses to MC-38 colorectal cancer

“…The method used for the mice treated with anti-PD-L1 antibodies can be found in the publication of Sow, H.S. et al 23 Vaccinated mice were injected once with 20 nmol Adpgk or Rpl18 synthetic peptides intradermally in 50 µL PBS adjuvanted with 20 µg of CpG (ODN 1826 – TLR9 ligand InvivoGen tlrl-1826-1) or 10 nmol Rpl18-conjugated with equimolar Upam-ligand (peptides and Upam where conjugated as described previously in). 24 – 26 …”

“…Tumor sizes where measured 2-3 times a week and 1500 mm 3 was maintained as humane endpoint. The method used for the mice treated with anti-PD -L1 antibodies can be found in the publication of Sow, H. S. et al 23 Vaccinated mice were injected once with 20 nmol Adpgk or Rpl18 synthetic peptides intradermally in 50 µL PBS adjuvanted with 20 µg of CpG (ODN 1826 -TLR9 ligand InvivoGen tlrl-1826-1) or 10 nmol Rpl18-conjugated with equimolar Upam-ligand (peptides and Upam where conjugated as described previously in). [24][25][26] In vitro (re-)stimulation T cell cultures were started with splenocytes from several experiments.…”