Cytokines, chemokines and their receptors in regulation of responses to anticancer therapies in Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer incidence. Non-small cell lung cancer (NSCLC) accounts for ~85% of cases; the main sub-classifications being lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). The tumour microenvironment (TME) plays a key role in NSCLC development and therapeutic response. NSCLC outcomes have significantly improved through the development of immune checkpoint inhibitors (ICI) that target the PD-1/PD-L1 checkpoint axis. However, not all patients respond and therefore there is interest in understanding mechanisms of resistance to allow patient stratification and develop novel combinations that may improve ICI efficacy.

Chemo-cytokines are small molecules secreted by many cells including immune cells. They are involved in the immune response and affect the TME phenotype and therapeutic response.

This PhD aimed to identify chemo-cytokines highly expressed in NSCLC and investigate the role of these in α-PD-1 therapy response.

The Cancer Genome Atlas database analysis combined with the Meso Scale Discovery protein assay analysis showed that the cytokine TXLNA and the chemokine CXCL1 were highly expressed in LUAD and LUSC. Their cognate receptors STX3 and CXCR2 were studied further.

Multi-immunofluorescence showed high expression of STX3 in mast cells, neutrophils, and epithelial cells. CXCR2 was highly expressed in macrophages, monocytes, and neutrophils.

Using NSCLC patient derived explants treated with α-PD-1 therapies pembrolizumab and nivolumab, a significant positive correlation was found between the percentage of STX3- expressing neutrophils in LUAD, STX3-expressing mast cells in LUSC and cell death response. A significant negative correlation was found between the percentage of CXCR2-expressing macrophages, neutrophils and cell death response in LUSC. Furthermore, STX3-expressing mast cells and CXCR2-expressing neutrophils were found to migrate to the tumour edge when treated. Our findings propose the TXLNA/STX3 axis and CXCL1/CXCR2 axis could potentially be used as stratification biomarkers and/or combination therapy targets in the treatment of NSCLC with α-PD-1 therapies.