PD-L1 expression in small cell neuroendocrine carcinomas

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Small cell lung cancer and extrapulmonary small cell carcinomas are aggressive neuroendocrine tumors with frequent relapses after chemotherapy and radiotherapy.
• The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is a key target in cancer immunotherapy, as aberrant expression can suppress anti-tumor immunity.

Purpose of the Study:

• To investigate the expression of PD-1 and its ligands (PD-L1 and PD-L2) in small cell carcinomas using immunohistochemistry and RNA sequencing.
• To determine if PD-1 pathway activation in the tumor microenvironment correlates with specific immune cell infiltrates.

Main Methods:

• Immunohistochemistry was used to analyze PD-1 and PD-L1 protein expression in 94 small cell carcinoma cases.
• RNA sequencing (RNA-seq) was performed on 43 cases to profile gene expression of PD-1 ligands.
• Correlations between PD-L1/PD-L2 expression and markers for tumor-infiltrating macrophages and lymphocytes were assessed.

Main Results:

• Tumor cells in all analyzed small cell carcinomas were negative for PD-L1 protein expression.
• PD-L1 protein was detected in tumor-infiltrating macrophages (18.5%) and PD-1 was found on lymphocytes (48%).
• RNA-seq revealed moderate PD-L1 gene expression in 37.2% of cases, correlated with macrophage and T-cell markers. PD-L2 gene expression was observed in 27.9% of cases.

Conclusions:

• The PD-1/PD-L1 pathway is activated within the tumor microenvironment of a subset of small cell carcinomas, primarily involving macrophages and lymphocytes, not tumor cells.
• Stromal PD-L1/PD-L2 expression may predict response to anti-PD-1 immunotherapy in small cell carcinomas.
• RNA-seq is a sensitive method for detecting PD-1 ligand expression and evaluating the tumor microenvironment composition in clinical trials.