CXCR4 and PD-1 Expression in Head and Neck Cancer with Perineural Spread

Background In advanced skin cancer and head and neck cancer, branches of the trigeminal and facial nerves are the most common nerves to demonstrate large nerve perineural spread (PNS), typically with spread proximally toward the skull base. These patients demonstrate higher rates of locoregional failure, distant metastases, and lower overall survival. CXCR4, a chemokine receptor, and its ligand CXCL12 have been shown to play a central role in the neurotropism of cancer cells to local peripheral nerves. CXCR4 has been significantly associated with distant metastases in head and neck cancer patients. Subsequently, blockade of the receptor was found to decrease cell migration and proliferation. The inhibition of this pathway has the potential to be targeted as a future treatment or biomarker, such as with use of a CXCR4 antagonist which has been used successfully in other tumors with perineural spread and CXCR4 overexpression. PD-1 is a cell surface receptor that has been shown to have poorer outcomes in a variety of cancers when overexpressed. There has also been evidence to show that blockade of the PD-1 pathway is associated with lasting benefits in tumor control. Specimens from previously treated PNS patients have been kept in tissue bank for future investigation of any potential biomarkers or therapeutic agents.

Objective Confirm that CXCR4 and PD-1 overexpression occurs in a subset of head and neck tumors that demonstrated perineural spread of cranial nerves.

Methods Retrospective immunohistochemical staining for the CXCR4 and PD-1 receptors was performed on nine head and neck PNS specimens from January 2017 to August 2017, at Royal Brisbane and Women's Hospital (RBWH), Brisbane, Australia. Ethics approval was provided by the RBWH Human Research Ethics Committee.

Results CXCR4 staining was strongly positive in 67% of the head and neck PNS specimens (6/9). Four of these specimens were squamous cell carcinoma, while two were adenoid cystic carcinoma. Tumors that were more histologically aggressive demonstrated more intense staining. In particular, the histologically aggressive adenoid cystic carcinoma tumors showed a pattern of staining that was distinctly different to the SCC tumors. In contrast, no significant staining for PD-1 in peritumoral lymphocytes or tumor specimens was seen (0/9).

Conclusion These results indicate that CXCR4 is overexpressed in advanced skin cancer and head and neck tumors that demonstrated perineural spread to large cranial nerves. Despite being overexpressed in a variety of other cancers, PD-1 was not significantly overexpressed in these specimens. Overall, these results provide strong support for a trial of immunotherapeutic agents that could inhibit tumor progression via targeting CXCR4 expression for patients with perineural spread in advanced head and neck cancer. This pilot study will be followed by a large retrospective study with specimens from January 2012 to August 2017.