It appears that, at least in breast cancer, therapeutic combinations directed against immune regulatory mechanism (i.e. checkpoint blockade, IL-23/Th17, TAM receptor kinases, hypoxia factors or IDO inhibitors) will modulate and possibly enhance responsiveness of cancers with CIRes (immune active cluster) but will be unlikely to work in the context of immune silent cancers of the PIRes phenotype unless complimentary efforts are made to disrupt the non-immunogenic landscape to convert it into an immunogenic one. This evidence concerns the gene IDO1 and breast cancer.