PD‐1 expression by canine T cells and functional effects of PD‐1 blockade

Abstract

The co-inhibitory checkpoint molecule programmed death receptor 1 (PD-1) can trigger T cell functional exhaustion upon binding to its ligand PD-L1 expressed on tumour cells or macrophages. PD-1 blocking antibodies have generated remarkable results in human cancer patients, including inducing durable responses in a number of advanced cancers. Therefore, monoclonal antibodies specific for canine PD-1 were assessed for T cell binding and induction of functional activation. A total of 5-10% of CD4 T cells and 20-25% of CD8 T cells from healthy dogs expressed PD-1, and PD-1 expression was upregulated on T cells from dogs with cancer. Functionally, PD-1 antibodies significantly enhanced T-cell activation, as assessed by proliferation and interferon-gamma (IFN-) production. PD-1 antibodies also reversed T-cell suppression induced by canine soluble PD-L1 and by tumour cells and tumour explant fragments. These findings indicate that PD-1 antibodies have potential for use in cancer immunotherapy in dogs.

Checkpoint molecule expression by B and T cell lymphomas in dogs

“…Murine anti‐canine PD‐1 (clone 3B6) and PD‐L1 (clone 5F12) monoclonal antibodies developed by Merck Research Laboratories (Kenilworth, New Jersey), described recently, were used for flow cytometry and immunofluorescence staining. An isotype matched, irrelevant antibody was used at the same concentrations for each study (eBioscience, San Diego, California).…”

“…We and others have reported that PD‐1 blocking antibodies can enhance activation of canine T cells in vitro . We also found that PD‐1 expression was significantly upregulated by T cells from dogs with cancer compared to healthy age‐matched animals .…”

“…PD‐1 antibody immunotherapy is now approved for treatment of melanoma, kidney cancer, non‐small cell lung cancer, head and neck cancer, Hodgkin lymphoma and urothelial cancer in humans . We, and others, have reported that PD‐1 antibodies can activate canine T cells, stimulating proliferation and cytokine production …”

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

“…Blocking the PD‐1/PD‐L1 pathway with an anti‐PD‐1 or PD‐L1 antibody can restore multiple effector functions of antigen‐specific T cells, overcoming immune escape mechanisms by cancer cells . In dogs, PD‐1 and PD‐L1 expression have been reported in sarcomas, specifically hemangiosarcoma and osteosarcoma, but the therapeutic potential of PD‐1/PD‐L1blockade has not yet been fully elucidated . Recently, a novel rat‐dog chimeric anti‐PD‐L1 monoclonal antibody (c4G12) was tested in vitro and enhanced cytokine production and proliferation of dog peripheral mononuclear cells.…”

“…135,136 In dogs, PD-1 and PD-L1 expression have been reported in sarcomas, specifically hemangiosarcoma and osteosarcoma, but the therapeutic potential of PD-1/PD-L1blockade has not yet been fully elucidated. 29,30,129,133,[137][138][139] Recently, a novel rat-dog chimeric anti-PD-L1 monoclonal antibody Objective tumour responses in one dog from each tumour category were observed when c4G12 was given intravenously biweekly at 2 or 5 mg/kg. 30 PD-L1 expression was confirmed in the primary tumours of these dogs prior to enrollment.…”