A Folate Receptor β‑Targeted TLR7 Agonist Significantly Augments Checkpoint Inhibitor Potencies by Reprogramming Tumor-Associated Macrophages and Myeloid-Derived Suppressor Cells

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.