Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Anatomy and Cell Biology

Supervisor

Penuela Silvia

2nd Supervisor

Qi Zhang

Co-Supervisor

Abstract

Brain metastases (BMs) are the leading cause of cancer-related deaths, comprise the majority of central nervous system malignancies, and widely originate from non-small lung carcinomas (NSCLC). Immunotherapy, particularly checkpoint inhibitors, has emerged as the standard of care for most patients with advanced lung cancer. Pannexin1 (PANX1) is a transmembrane glycoprotein that forms large-pore channels and has been reported to promote tumorigenesis in metastatic cancers. However, the roles of PANX1 in lung cancer-associated brain metastases and tumor-infiltrating lymphocytes have not been identified. Forty-two patient-matched formalin-fixed paraffin-embedded tissue samples from lung carcinomas and subsequent brain metastases were constructed into two master-tissue microarrays (TMAs). PANX1, PD-L1, and tumor-infiltrating immune cells (CD3+, CD4+, CD8+, and CD68+) were assessed using immunohistochemistry and digital image analysis (QuPath software). The expression of PANX1 was significantly higher in brain metastases than paired primary lung carcinoma. Strikingly, the level of PANX1 in lung carcinoma cells in the brain correlated negatively with the infiltration density of blood-derived macrophages. Our findings highlight the role of PANX1 in the progression of metastatic NSCLC, and the potential therapeutic approach of targeting PANX1 enhances the efficacy of immune checkpoint inhibitors in brain metastasis.

Summary for Lay Audience

Cancer from other parts of the body can spread to the brain. This is known as brain metastasis, the leading cause of cancer-related deaths. Brain metastases comprise the majority of brain tumors and widely originate from lung cancer. Immunotherapy approaches have emerged as the standard of care for most patients with advanced lung cancer. However, the difference in brain metastasis progress and response to immunotherapies among lung cancer patients requires robustly predictive- cellular parameters. Pannexin1 (PANX1) is a cellular protein that forms large-pore channels and has been reported to promote aggressiveness in multiple cancers. The roles of PANX1 in brain metastasis and immune responses have not been identified. Therefore, we studied 42 patient specimens obtained from lung cancers and their migratory cells in the brain and eventually conducted biological staining to assess the profiles of PANX1 and immune cells within cancer compartments. We found that PANX1 was higher in brain metastases compared to primary lung cancer. Immune cells known as macrophages that digest harmful structures and/or present them to T cells (cancer cells’ killers) were less in brain metastasis cases with high levels of PANX1. These findings indicate the role of PANX1 in cancer progression and the immunological profile of advanced lung cancer.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Download

Share

COinS