Learning from PD-1 Resistance: New Combination Strategies

Abstract

Only a minority of cancer patients respond to anti PD-1 immunotherapy. A recent study demonstrates that PD-1 therapy-resistant melanoma patients present distinct signatures of upregulated genes involved in immunosuppression, angiogenesis, monocyte and macrophage chemotaxis, extracellular matrix remodeling, and epithelial-mesenchymal transition (EMT). Combination targeting of these pathways with PD-1 may help overcome PD-1 resistance, thus producing effective antitumor immunity.

Figure 1.. The Innate PD-1 Resistance (IPRES) Signature.

Data from the Hugo et al. study reveal upregulated expression of gene sets associated with wound healing, angiogenesis, hypoxia, TGF-beta signaling, epithelial-mesenchymal transition (EMT), as well as cell adhesion and extracellular matrix organization in nonresponding melanoma tumors from patients undergoing anti-PD-1 treatment. Nonresponder tumors express less CDH1 (E-cadherin, a marker of differentiated epithelia) than responder tumors. The IPRES signature includes genes involved in immunosuppression (IL10) and angiogenesis (VEGFA, VEGFC, FLT1, and ANGPT2), monocyte and macrophage chemotaxis (CCL2, CCL7, CCL8, CCL13) and EMT (AXL, ROR2, WNT5A, LOXL2, TWIST2, TAGLN, FAP). DC; dendritic cells; MDSC, myeloid derived suppressor cells; VEGFR, vascular endothelial growth factor receptor.