Immune checkpoint inhibition of program death protein-1 (PD-1) and its ligands PD-L1 and PD-L2 is an established therapeutic modality in melanoma, non-small cell lung cancer, renal cell carcinoma, and other tumor types. Unfortunately, 60 to 80% of all patients experience disease progression and become refractory to immune checkpoint therapies. Broadly, mechanisms of immune checkpoint inhibitor resistance can be categorized as presence of oncogenic driver mutations, severe T cell exhaustion, neoantigen burden, epigenetic alterations, or mutations involved in critical pathways including PTEN, JAK, or Wnt signaling. The dysregulation of inflammatory signaling pathways (namely, genes involved in angiogenesis, chemotaxis, matrix remodeling, wound healing, and mesenchymal transition) is of critical importance to response to immune checkpoint therapies. Inflammatory cytokine signaling pathways exert downstream effects on immunosuppressive elements such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) which inhibit the function of effector T cells, NK cells, and dendritic cells, promoting immune tolerance and tumor growth. We herein review three targets for inflammatory pathway modulation: indoleamine 2,3-dioxygenase (IDO), transforming growth factor β (TGFβ), and adenosine. Targeting these pathways may address the unmet need to develop novel therapeutic approaches to increase response rates to immune checkpoint inhibitors and improve clinical outcomes.
