Immune checkpoint inhibitors (ICIs) such as anti-PD-L1
antibodies are widely used to treat human
cancers, and growing evidence suggests that ICIs are promising treatments for canine
malignancies. However, only some canine oral
malignant melanoma (OMM) cases respond to ICIs. To explore
biomarkers predictive of survival in dogs with pulmonary metastatic OMM receiving the anti-PD-L1 antibody c4G12 (n = 27), serum concentrations of
prostaglandin E2 (
PGE2),
cytokines,
chemokines, and
growth factors were measured prior to treatment initiation. Among 12 factors tested,
PGE2,
interleukin (IL)-12p40,
IL-8,
monocyte chemotactic protein-1 (MCP-1), and
stem cell factor (SCF) were higher in OMM dogs compared to healthy dogs (n = 8). Further, lower baseline serum
PGE2, MCP-1, and
vascular endothelial growth factor (
VEGF)-A concentrations as well as higher
IL-2,
IL-12, and SCF concentrations predicted prolonged overall survival. These observations suggest that
PGE2 confers resistance against anti-PD-L1
therapy through immunosuppression and thus is a candidate target for combination
therapy. Indeed,
PGE2 suppressed
IL-2 and
interferon (IFN)-γ production by stimulated canine peripheral blood mononuclear cells (PBMCs), while inhibition of
PGE2 biosynthesis using the
COX-2 inhibitor meloxicam in combination with c4G12 enhanced Th1
cytokine production by PBMCs. Thus, serum
PGE2 may be predictive of c4G12 treatment response, and concomitant use of
COX-2 inhibitors may enhance ICI antitumor efficacy.