TMIC-34. Na/H EXCHANGER ISOFORM 1 (NHE1) IN IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT IN MOUSE SYNGENEIC GLIOMA MODEL
Year: 2018
Type: conference-abstract
Abstract: Glioblastoma is the most common and aggressive brain tumor with a median survival of ~15 months. Clinical trials of patients for immunotherapy showed an inferior response, which can in part attribute to an immunosuppressive, acidic tumor microenvironment (TME) composed of glioma-associated microglia/macrophages (TAMs), regulatory T-cells (Treg), and expression of immune checkpoint molecules. NHE1 maintains alkaline pHi in glioma and TAMs, promoting their migration and proliferation. Temozolomide (TMZ) therapy concurrently induces upregulation of NHE1 in glioma and alters TME immunogenicity. In this study, we investigated the impact of selective deletion of Nhe1 from microglia/macrophage using Cx3Cr1CreEr+/-;Nhe1f/f mice (Nhe1 KO). Non-immunogenic SB28-GFP glioma cells were transplanted intracranially, and tamoxifen (75 mg/kg, i.p.) was administered at 1–5 days post-glioma injection (d.p.i.). Cx3Cr1CreEr-/-;Nhe1f/f mice receiving identical treatment served as controls (Con). These mice were subsequently treated with DMSO or TMZ (2.5 mg/kg, i.p.) at 2–6 d.p.i. TAM infiltration and T-cell profile were analyzed by flow-cytometry at 10 d.p.i. TMZ monotherapy in Con mice elevated the tumor infiltrated microglia by 2-fold and macrophage numbers by 2.5-fold. In contrast, Nhe1 KO mice treated with TMZ did not exhibit a significant increase of microglia or macrophage infiltration. Ym-1+ tolerogenic macrophages in tumors from TMZ-treated Nhe1 KO mice were nearly abolished. TMZ treatment in Nhe1 KO mice also reduced the tumor-promoting CD4+CD25+FoxP3+ Treg infiltration but did not change CD8+GZMb+ and CD8+IFNγ+ populations. Moreover, combining TMZ with selective deletion of Nhe1 in Cx3Cr1+ cells significantly elevated CD4+PD-1+ and CD8+PD-1+ cell population. Most importantly, Nhe1 KO mice treated with combinatorial TMZ and anti-PD-1 therapy prolonged the animal survival. Taken together, our study suggests that NHE1 is involved in modulating TME and PD-1 expression. Blockade of NHE1 function in combination with TMZ and anti-PD-1 could improve TME and provide an alternative treatment strategy for glioblastoma. This was supported by NIH-grant R01NS75995(DS).
Source: Neuro-Oncology
Institution: University of Pittsburgh
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2899762311