The HER2 gene, located adjacent to the topoisomerase IIa genes, is related to the oncogene v-erbB of the avian erythroblastosis virus. In carcinomas, HER2 acts as an oncogene, mainly because highlevel amplification of the gene induces protein overexpression in the cellular membrane and subsequent acquisition of advantageous properties for a malignant cell.
A role of HER2 in the development of numerous types of human cancer has been indicated by many studies. HER2 overexpression and/or amplification have been detected in 10%–34% of invasive breast cancers and correlate with the clinical outcome, confer poor prognosis, and also constitute a predictive factor of poor response to chemotherapy and endocrine therapy. HER2 overexpression and/or amplification have also been observed in colon, bladder, ovarian, endometrial, lung, uterine cervix, head and neck, esophageal, and gastric carcinomas.
Programmed death 1 (PD-1) is a key immune-checkpoint receptor expressed by activated T cells, and it mediates immunosuppression. PD-1 functions primarily in peripheral tissues, where T cells may encounter the immunosuppressive PD-1 ligands PD-L1 (B7-H1) and PD-L2 (B7-DC), which are expressed by tumor cells, stromal cells, or both. Inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity.
Growth of solid tumours is accompanied by stimulation of angiogenesis. Vascular endothelial growth factor-A (VEGFA; also referred to as VEGF) is one, but not the only, primary factor driving expansion of the tumour vascular bed. It is well established that the tumour microvasculature displays abnormal features, including high turnover of vessels, poor perfusion and increased leakage. In many instances vascular 'normalization', i.e. reversal of these abnormalities in response to antiangiogenic treatment, has been reported to lead to decreased tumour growth, despite the fact that the normalized tumour vessels appear more functional.
Claesson‐Welsh L, Welsh M. VEGFA and tumour angiogenesis[J]. Journal of internal medicine, 2013, 273(2): 114-127.
Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target[J]. Annals of Oncology, 2008, 19(9): 1523-1529.