Adenosine Pathway Activation Defines Genetically Linked Immunosuppressive Subtypes in Solid Tumor Brain Metastases.

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Brain metastases present an immunosuppressive microenvironment, limiting PD-1/PD-L1 inhibitor efficacy.
• The adenosine pathway (CD39/CD73) is an emerging immune escape mechanism in cancer.
• Its role in diverse brain metastases remains unclear.

Purpose of the Study:

• To characterize the adenosine pathway's relevance in brain metastases across various primary tumor types.
• To integrate genetic alterations with immune marker expression (CD39, CD73, PD-L1).
• To define immunogenomic subtypes for improved immunotherapy strategies.

Main Methods:

• Targeted panel sequencing of brain metastases from multiple primary tumor entities.
• Compartment-resolved immunohistochemistry for CD39, CD73, and PD-L1 expression.
• Analysis of tumor mutational burden (TMB), gene alterations, and fusions.

Main Results:

• Brain metastases show heterogeneous mutations (e.g., TP53, KRAS, PIK3CA, APC).
• CD39 and CD73 expression is frequent on tumor and immune cells, with variable overlap with PD-L1.
• An adenosine-high phenotype exists independently of PD-L1, linked to specific genetic alterations.

Conclusions:

• Adenosine pathway activation is a common, genetically linked immune escape mechanism in brain metastases.
• Combining CD39/CD73 and PD-L1 expression refines immunogenomic subtyping.
• This approach supports developing targeted immunotherapies for adenosine-mediated immunosuppression.