Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy.

Abstract

The weak immunogenicity of gliomas presents a barrier for effective immunotherapy. Na/H exchanger isoform 1 (NHE1) maintains alkaline intracellular pH (pHi) of glioma cells and acidic microenvironment. In addition, NHE1 is expressed in tumor-associated microglia and tumor-associated macrophages (TAMs) and involved in protumoral communications between glioma and TAMs. Therefore, we hypothesize that NHE1 plays a role in developing tumor resistance and immunosuppressive tumor microenvironment. In this study, we investigated the efficacy of pharmacological inhibition of NHE1 on combinatorial therapies. Here we show that temozolomide (TMZ) treatment stimulates NHE1 protein expression in two intracranial syngeneic mouse glioma models (SB28, GL26). Pharmacological inhibition of NHE1 potentiated the cytotoxic effects of TMZ, leading to reduced tumor growth and increased median survival of mice. Blockade of NHE1 stimulated proinflammatory activation of TAM and increased cytotoxic T cell infiltration into tumors. Combining TMZ, anti-PD-1 antibody treatment with NHE1 blockade significantly prolonged the median survival in the mouse glioma model. These results demonstrate that pharmacological inhibition of NHE1 protein presents a new strategy for potentiating TMZ-induced cytotoxicity and increasing tumor immunogenicity for immunotherapy to improve glioma therapy.

• Authors: Xiudong Guan, Md Nabiul Hasan, Gulnaz Begum, Gary Kohanbash, Karen E Carney, Victoria M Pigott, Anders I Persson, Maria G Castro, Wang Jia, Dandan Sun
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 10 Pg. 1010 (09 27 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 30262908 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Slc9a1 protein, mouse
• Sodium-Hydrogen Exchanger 1
• Temozolomide

Topics

• Animals
• Antibodies (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Female
• Glioma (drug therapy, metabolism)
• Immunotherapy (methods)
• Macrophages (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, metabolism)
• Sodium-Hydrogen Exchanger 1 (metabolism)
• T-Lymphocytes, Cytotoxic (drug effects, metabolism)
• Temozolomide (pharmacology)
• Tumor Microenvironment (drug effects)