EZH1/2 inhibition improves immunotherapy response through MHC Class II de-repression and neutrophil reprogramming

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Lung squamous cell carcinoma (LSCC) is a prevalent and challenging cancer.
• Current immunotherapies like anti-PD1 have limited efficacy in LSCC.
• EZH1/2 inhibitors are being explored as potential sensitizers for immunotherapy.

Purpose of the Study:

• To evaluate if the EZH1/2 inhibitor valemetostat enhances anti-PD1 therapy responses in LSCC models.
• To develop and utilize ex vivo models for testing immunotherapy combinations.
• To investigate the role of neutrophils and Major Histocompatibility Complex Class II (MHC Class II) in LSCC response to therapy.

Main Methods:

• In vivo studies using LSCC mouse models treated with valemetostat and anti-PD1 therapy.
• Ex vivo three-dimensional air-liquid interface cultures with tumoroids, lung mesenchymal cells, T cells, and bone marrow-derived neutrophils.
• Analysis of neutrophil maturation, apoptosis, migration, and bacterial killing capacity.
• Assessment of MHC Class II expression on tumor cells and its blockade.
• Correlation analysis of EZH2 and MHC Class II expression in patient samples.

Main Results:

• Valemetostat combined with anti-PD1 therapy demonstrated augmented anti-tumor responses.
• This combination therapy led to increased tumor cell MHC Class II expression and activated CD8+ T cells.
• Neutrophil maturation was associated with tumor rejection and response to valemetostat treatment.
• Ex vivo models showed that bone marrow from treated or tumor-rejected mice had anti-tumor properties.
• MHC Class II blockade diminished the bone marrow's tumor-boosting capacity and reduced the efficacy of combined therapy.

Conclusions:

• Valemetostat enhances anti-PD1 immunotherapy in LSCC by upregulating MHC Class II and promoting T cell activation.
• Neutrophil maturation plays a critical role in anti-tumor immunity and response to EZH1/2 inhibition.
• Targeting EZH2 activity may represent a viable strategy to increase MHC Class II expression and improve immunotherapy outcomes in LSCC.
• Developed ex vivo models provide a platform for future immunotherapy drug combination studies.