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Extracellular pH modulating injectable gel for enhancing immune checkpoint inhibitor therapy
- Source :
- Journal of Controlled Release. 315:65-75
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Clinical data from diverse cancer types shows that the increased T cell infiltration in tumors correlates with improved patient prognosis. Acidic extracellular pH is a major attribute of the tumor microenvironment (TME) that promotes immune evasion and tumor progression. Therefore, antagonizing tumor acidity can be a powerful approach in cancer immunotherapy. Here, Pluronic F-127 is used as a NaHCO3 releasing carrier to focally alleviate extracellular tumor acidity. In a mouse tumor model, intratumoral treatment with pH modulating injectable gel (pHe-MIG) generates immune-favorable TME, as evidenced by the decrease of immune-suppressive cells and increase of tumor infiltrating CD8+T cells. The combination of pHe-MIG with immune checkpoint inhibitors, anti-PD-1 and anti-TIGIT antibodies, increases intratumoral T cell function, which leads to tumor clearance. Mechanistically, extracellular acidity was shown to upregulate co-inhibitory immune checkpoint receptors and inhibit mTOR signaling pathways in memory CD8+T cells, which impaired effector functions. Furthermore, an acidic pH environment increased the expression and engagement of TIGIT and its ligand CD155, which suggested that the extracellular pH can regulate the suppressive function of TIGIT pathway. Collectively, these findings suggest that pHe-MIG holds potential as a new TME modulator for effective immune checkpoint inhibitor therapies.
- Subjects :
- Male
medicine.medical_treatment
T cell
Programmed Cell Death 1 Receptor
Pharmaceutical Science
Poloxamer
02 engineering and technology
CD8-Positive T-Lymphocytes
Mice
03 medical and health sciences
Immune system
TIGIT
Cancer immunotherapy
Neoplasms
Tumor Microenvironment
medicine
Animals
Humans
Receptors, Immunologic
030304 developmental biology
Drug Carriers
0303 health sciences
Tumor microenvironment
Chemistry
TOR Serine-Threonine Kinases
Immunotherapy
Hydrogen-Ion Concentration
021001 nanoscience & nanotechnology
Immune checkpoint
Mice, Inbred C57BL
medicine.anatomical_structure
Tumor progression
Cancer research
0210 nano-technology
Gels
Subjects
Details
- ISSN :
- 01683659
- Volume :
- 315
- Database :
- OpenAIRE
- Journal :
- Journal of Controlled Release
- Accession number :
- edsair.doi.dedup.....e9c2624513f43de8db4f4ff19cdd6973