Combination of p38 MAPK inhibitor with PD-L1 antibody effectively prolongs survivals of temozolomide-resistant glioma-bearing mice via reduction of infiltrating glioma-associated macrophages and PD-L1 expression on resident glioma-associated microglia

Brain Tumor Pathol. 2021 Jul;38(3):189-200. doi: 10.1007/s10014-021-00404-3. Epub 2021 Jul 6.

Abstract

Current conventional treatment strategies for glioblastoma (GBM) have limited efficacy due to the rapid development of resistance to temozolomide (TMZ). It is particularly urgent to develop novel therapeutic strategies that can overcome TMZ resistance and provide patients with better prognoses. Here, a TMZ-resistant GBM cell strain and a mouse model of TMZ resistance are established as valuable tools to explore novel therapeutic strategies against TMZ resistance. Experimentally, p38MAPK inhibitor reduces the accumulation of F4/80+/CD11b+ macrophages/microglia in glioma and prolongs the survivals of glioma-bearing mice. Glioma-associated macrophages/microglia have a significanct expression of PD-L1. p38MAPK inhibitor in combination with PD-L1 antibody can effectively prolongs the survivals of TMZ-resistant GBM-bearing hosts, and differentially reduces the accumulation of circulating monocytes-derived tumor-associated macrophages and PD-L1 abundances of resident glioma-associated microglia. This combination therapy could be a treatment option for patients at the recurrence or chronic TMZ maintenance stages. A clinical study to confirm the safety and effectiveness of this combination therapy is warranted.

Keywords: Glioma-associated macrophages; Glioma-associated microglia; PD-L1; Temozolomide-resistant; p38 MAPK.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Antineoplastic Agents, Alkylating / therapeutic use
  • B7-H1 Antigen / genetics*
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Drug Therapy, Combination
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / genetics*
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics*
  • Glioblastoma / mortality
  • Glioblastoma / pathology*
  • Humans
  • Mice
  • Microglia / metabolism*
  • Survival Rate
  • Temozolomide / pharmacology*
  • Tumor-Associated Macrophages / pathology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents, Alkylating
  • B7-H1 Antigen
  • Enzyme Inhibitors
  • p38 Mitogen-Activated Protein Kinases
  • Temozolomide