Although immune checkpoint inhibition has emerged as a promising treatment for many solid tumors, infiltrating immune cells, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), can limit their potencies. To address this issue, we used folic acid to target a Toll-like receptor 7 (TLR7) agonist to folate receptor β (FRβ) expressing TAMs and MDSCs, with the anticipation that repolarization of these myeloid cells to tumoricidal phenotypes might restore the intrinsic potencies of checkpoint inhibitors. We demonstrate that this folate-TLR7 conjugate can not only reprogram FRβ-expressing myeloid cells in the tumor microenvironment (TME) but can also induce a global shift in the TME to an inflammatory state. We then demonstrate that TME repolarization significantly enhances the potencies of both anti-PD-1 and anti-CTLA-4 checkpoint inhibitors in multiple tumor models and conclude that the reprogramming of TAMs/MDSCs to a tumoricidal phenotype can significantly augment the potencies of checkpoint inhibitors without causing toxicity to healthy tissues.
Napoleon et al. (Tue,) studied this question.