Remodeling the Tumor Microenvironment Sensitizes Breast Tumors to Anti-Programmed Death-Ligand 1 Immunotherapy

Cancer Res. 2019 Aug 15;79(16):4149-4159. doi: 10.1158/0008-5472.CAN-18-3060. Epub 2019 Jun 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / immunology
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Hyaluronic Acid / metabolism
  • Hyaluronoglucosaminidase / metabolism
  • Hyaluronoglucosaminidase / pharmacology*
  • Immunotherapy / methods*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / pathology
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / therapy*
  • Mice, Inbred BALB C
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / pathology
  • Tumor Microenvironment / drug effects*

Substances

  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Hyaluronic Acid
  • Hyaluronoglucosaminidase
  • PEGPH20