Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors

Key Points Tumours dominantly suppress anti-tumour immunity through various pro-toleragenic mechanisms. A particularly attractive approach to target these mechanisms might be through the development of small-molecule immunotherapeutic drugs. The indoleamine 2,3-dioxygenase (IDO) enzyme, which catabolizes the essential amino acid tryptophan, promotes tumoral immune tolerance by blocking the activation of effector T cells. Cancer cells express IDO, as do antigen-presenting dendritic cells that are present in tumour-draining lymph nodes, and both might contribute to immune escape. A small-molecule IDO inhibitor is in preclinical development. The arginase (ARG)1 enzyme, which is expressed by tumour cells, myeloid suppressor cells and tumour-associated macrophages, has been implicated in suppressing anti-tumour immunity through catabolism of the amino acid arginine. Inducible nitric-oxide synthase (iNOS), another enzyme that catabolizes arginine, generally shows reciprocal regulation to ARG. However, in the context of some tumours, increased expression of both enzymes might contribute to immune suppression. Nitroaspirin, which inhibits both enzymes, is currently the most promising small molecule in development. The cyclooxygenase 2 (COX2) enzyme has a central role in regulating the mechanisms of immune suppression and promotes the generation of regulatory T cells. Selective COX2 inhibitors have demonstrated evidence of additional clinical benefit in combination with chemotherapeutic agents, but recent concerns over safety have slowed testing. Inhibitors that target the prostaglandin receptors might represent an alternative. The transforming growth factor β (TGFβ) cytokine can have profound immunosuppressive effects, and cancer cells adapt by becoming refractory to TGFβ signalling. Several approaches aimed at inhibiting TGFβ signalling are currently being investigated in terms of therapeutic potential, including small-molecule inhibitors of the TGFβ receptor tyrosine kinase. Targeting downstream Janus kinase (JAK)–signal-tansducer-and-activator-of-transcription (STAT) signalling pathways might be an option for interfering with toleragenic cytokine activity, as might the vascular-endothelial-growth-factor (VEGF) receptor FMS-related tyrosine kinase 1 (FLT1), which can promote defective dendritic-cell maturation. Chemokines have also been implicated in the recruitment of immunosuppressive effector cell types to the local tumour microenvironment. Small-molecule inh