Abstract
Immunotherapies targeting immune checkpoint inhibitors have changed the landscape of cancer treatment, however, many patients are resistant or refractory to immunotherapy. The sensitivity of tumor cells to immunotherapy may be influenced by hyaluronan (HA) accumulation in the tumor microenvironment (TME). Enzymatic degradation of HA by pegvorhyaluronidase alfa (PEGPH20; PVHA) remodels the TME. This leads to reduced tumor interstitial pressure and decompressed tumor blood vessels, which are both associated with increased exposure of tumor cells to chemotherapy drugs. Here, we demonstrate PVHA increased the uptake of anti-programmed death-ligand 1 (PD-L1) antibody in HA-accumulating animal models of breast cancer. The increased levels of anti-PD-L1 antibody were associated with increased accumulation of T cells and natural killer cells and decreased myeloid-derived suppressor cells. PD-L1 blockade significantly inhibited tumor growth when combined with PVHA, but not alone. Our results suggest that PVHA can sensitize HA-accumulating tumors to anti-PD-L1 immunotherapy. SIGNIFICANCE: These findings show removal of hyaluronan in the tumor microenvironment improves immune cells and checkpoint inhibitors access to tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4149/F1.large.jpg.
Highlights
Cancer immunotherapy using mAbs to target ligands [programmed death-ligand 1 (PD-L1)], receptors [programmed cell death protein 1 (PD-1), and cytotoxic T lymphocyte– associated protein 4 (CTLA-4)] of inhibitory immune checkpoints, which can be overexpressed by cancer cells, represents one of the biggest advances in cancer treatment in recent years
Our results suggest that PVHA can sensitize HA-accumulating tumors to anti-programmed deathligand 1 (PD-L1) immunotherapy
These findings show removal of hyaluronan in the tumor microenvironment improves immune cells and checkpoint inhibitors access to tumors
Summary
Cancer immunotherapy using mAbs to target ligands [programmed death-ligand 1 (PD-L1)], receptors [programmed cell death protein 1 (PD-1), and cytotoxic T lymphocyte– associated protein 4 (CTLA-4)] of inhibitory immune checkpoints, which can be overexpressed by cancer cells, represents one of the biggest advances in cancer treatment in recent years. Two anti-PD-1 mAbs [pembrolizumab (KEYTRUDA, Merck & Co., Inc.) and nivolumab (OPDIVO, Bristol-Myers Squibb Company)] and three anti-PDL1 mAbs [atezolizumab (TECENTRIQ, Genentech, Inc.), durvalumab (IMFINZI, AstraZeneca, Inc.), and avelumab (BAVENCIO, EMD Serono, Inc.)], have been approved by the FDA for clinical use in multiple tumors, and an anti-CTLA-4 mAb [ipilimumab (YERVOY, Bristol-Myers Squibb Company)] has been approved for the treatment of metastatic melanoma [2,3,4]. These antitumor responses may be enhanced by means of combinatorial strategies that are intelligently designed and guided by preclinical models [6]
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