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PPP2R2A insufficiency enhances PD-L1 immune checkpoint blockade efficacy in lung cancer through cGAS-STING activation
Zhaojun Qiu1, No-Joon Song2,3, Anqi Li2,3
1The Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, Ohio, USA.
Abstract:
PP2A B55α, a regulatory subunit of protein phosphatase 2 (PP2A), is underexpressed in greater than 40% of non-small cell lung cancer (NSCLC) cases due to loss of heterozygosity of PPP2R2A, the gene encoding this protein. Given that low PPP2R2A expression correlates with poor prognosis, treating PPP2R2A-deficient NSCLC represents an unmet medical need. Here, we show that PPP2R2A knockdown or its heterozygosity (PPP2R2A+/-) increases cytosolic DNA, leading to cGAS-STING-type I IFN pathway activation. PPP2R2A deficiency results in elevated expression of immune checkpoint protein PD-L1 via GSK-3β- and STING-dependent mechanisms. PPP2R2A+/- cancer cells have enhanced sensitivity to PD-L1 blockade in a mouse model of lung cancer due to modulation of the tumor immune microenvironment, resulting in increased NK cells and reduced infiltration and function of Tregs. Consequently, PD-L1 antibody treatment increases CD8+ T infiltration and activity, especially in tumors with PPP2R2A heterozygosity. Furthermore, systemic or Treg-specific IFNAR1 blockade reduces the efficacy of PD-L1 blockade in PPP2R2A+/- tumors. Patients with NSCLC with a low PPP2R2A/PD-L1 ratio respond better to immune checkpoint blockade (ICB). These findings underscore the therapeutic potential of ICB in treating PPP2R2A-deficient NSCLC and suggest that PPP2R2A deficiency could serve as a biomarker for guiding ICB-based therapies.
Insights
Protein phosphatase 2 (PP2A) B55α deficiency in non-small cell lung cancer (NSCLC) activates immune pathways and increases PD-L1. This suggests immune checkpoint blockade (ICB) is a promising therapy for PPP2R2A-deficient NSCLC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Protein phosphatase 2 (PP2A) B55α, encoded by PPP2R2A, is underexpressed in over 40% of non-small cell lung cancer (NSCLC) cases.
- Low PPP2R2A expression correlates with poor prognosis in NSCLC, indicating an unmet therapeutic need.
Purpose of the Study:
- To investigate the role of PPP2R2A deficiency in NSCLC pathogenesis and its implications for immunotherapy.
- To explore the potential of targeting the cGAS-STING pathway and PD-L1 in PPP2R2A-deficient NSCLC.
Main Methods:
- Utilized gene knockdown and heterozygosity models (PPP2R2A+/-) to study the effects of PPP2R2A deficiency.
- Analyzed cytosolic DNA accumulation, cGAS-STING-type I interferon (IFN) pathway activation, and PD-L1 expression.
- Assessed tumor immune microenvironment modulation and response to PD-L1 blockade in a mouse model of lung cancer.
Main Results:
- PPP2R2A deficiency leads to increased cytosolic DNA, activating the cGAS-STING-IFN pathway.
- PPP2R2A deficiency upregulates PD-L1 expression through GSK-3β- and STING-dependent mechanisms.
- PPP2R2A+/- tumors show enhanced sensitivity to PD-L1 blockade, with increased NK cells, reduced regulatory T cells (Tregs), and elevated CD8+ T cell activity.
Conclusions:
- PPP2R2A deficiency promotes an immune-suppressive tumor microenvironment that is responsive to PD-L1 blockade.
- The PPP2R2A/PD-L1 ratio may serve as a predictive biomarker for guiding immune checkpoint blockade (ICB) therapy in NSCLC patients.
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