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Updated: Jun 3, 2025
Measuring Phagosome pH by Ratiometric Fluorescence Microscopy
Published on: December 7, 2015
Acidic pH can attenuate immune killing through inactivation of perforin
Adrian W Hodel1, Jesse A Rudd-Schmidt2, Tahereh Noori2
1Killer Cell Biology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. adrian.hodel@petermac.org.
Abstract:
Cytotoxic lymphocytes are crucial to our immune system, primarily eliminating virus-infected or cancerous cells via perforin/granzyme killing. Perforin forms transmembrane pores in the plasma membrane, allowing granzymes to enter the target cell cytosol and trigger apoptosis. The prowess of cytotoxic lymphocytes to efficiently eradicate target cells has been widely harnessed in immunotherapies against haematological cancers. Despite efforts to achieve a similar outcome against solid tumours, the immunosuppressive and acidic tumour microenvironment poses a persistent obstacle. Using different types of effector cells, including therapeutically relevant anti-CD19 CAR T cells, we demonstrate that the acidic pH typically found in solid tumours hinders the efficacy of immune therapies by impeding perforin pore formation within the immunological synapse. A nanometre-scale study of purified recombinant perforin undergoing oligomerization reveals that pore formation is inhibited specifically by preventing the formation of a transmembrane β-barrel. The absence of perforin pore formation directly prevents target cell death. This finding uncovers a novel layer of immune effector inhibition that must be considered in the development of effective immunotherapies for solid tumours.
Insights
The acidic tumor microenvironment inhibits cytotoxic lymphocyte therapy by preventing perforin pore formation. This discovery reveals a new barrier to effective solid tumor immunotherapies.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Cytotoxic lymphocytes eliminate virus-infected and cancerous cells using perforin/granzyme-mediated killing.
- Perforin forms pores in target cell membranes, enabling granzyme entry and apoptosis induction.
- Current immunotherapies leverage cytotoxic lymphocytes effectively against hematological cancers but face challenges with solid tumors.
Purpose of the Study:
- To investigate the impact of the acidic tumor microenvironment on the efficacy of immune-mediated cell killing.
- To elucidate the specific mechanism by which acidic pH hinders cytotoxic lymphocyte function.
Main Methods:
- Utilized various effector cells, including anti-CD19 CAR T cells.
- Performed nanometre-scale studies on purified recombinant perforin oligomerization.
- Investigated perforin pore formation within the immunological synapse under acidic conditions.
Main Results:
- Acidic pH, characteristic of solid tumors, impedes perforin pore formation within the immunological synapse.
- Pore formation inhibition occurs specifically by preventing the transmembrane β-barrel structure.
- This blockage of perforin pore formation directly prevents target cell death.
Conclusions:
- The acidic tumor microenvironment presents a significant obstacle to anti-cancer immune therapies.
- Inhibition of perforin pore formation is a novel mechanism of immune effector suppression in solid tumors.
- Understanding this pH-dependent inhibition is crucial for developing more effective immunotherapies for solid tumors.
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