Immune Checkpoint Markers in Neuroendocrine Carcinoma of the Digestive System

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Digestive system neuroendocrine carcinomas (NECs) are rare, aggressive tumors with limited treatment options.
• Programmed cell death protein 1/ligand 1 (PD-1/PD-L1) blockade shows promise in various cancers, but its efficacy in NECs is unclear.
• Biomarkers like PD-L1 expression, tumor mutational burden (TMB), and microsatellite instability (MSI) predict response to immunotherapy.

Purpose of the Study:

• To investigate PD-L1 expression and immune cell infiltration in digestive system NECs.
• To evaluate tumor mutational burden (TMB) and microsatellite instability-high (MSI-H) status in these tumors.
• To assess the potential of anti-PD-1/PD-L1 therapy in digestive system NECs.

Main Methods:

• Immunohistochemical (IHC) staining was used to assess PD-L1 expression and immune cell infiltration (CD3+, CD8+, CD68+).
• Whole-exome sequencing was performed on tumor and normal samples to determine TMB and MSI status.
• Multiple bioinformatics tools (mSINGS, MSIsensor, MSIseq) were employed for MSI analysis.

Main Results:

• Positive PD-L1 expression was observed in 29.0% of digestive system NECs (Tumor Proportion Score).
• Significant infiltration of CD3+ (69.7%), CD8+ (27.3%), and CD68+ (54.5%) immune cells was detected.
• Median TMB was 5.68 mutations/Mb, and importantly, no MSI-high status was identified in any patient.

Conclusions:

• Digestive system NECs exhibit variable PD-L1 expression and immune cell infiltration.
• The absence of MSI-high status suggests limited benefit from MSI-targeting therapies.
• These findings indicate a potentially restricted role for PD-1/PD-L1 blockade monotherapy in digestive system NECs, warranting further clinical investigation.