Screening of Potential Therapeutic Targets for Cancer Immunotherapy based on Proven Immune Checkpoints and TCGA Database

Feiyu Wang
School of Molecular Biosciences, University of Glasgow, Glasgow, G12 8QQ, the UK

Abstract:

Cancer is severe disease that results in millions of deaths annually across the world. Immunotherapies, such as immune checkpoint inhibitors (ICI) are now become new choices for cancer treatment independently or combined with traditional chemo- and radiotherapy. However, the application of ICI now shows many drawbacks that limited its efficacy in cancer treatments with the accumulation of clinical data. To address this problem, the development of new ICI drugs against identified checkpoints, such as PD-1 and CTLA4, and the identification of new druggable targets are two rational solutions. Therefore, this paper focused on identifying new druggable targets based on early research of the basic biology of immune checkpoints with the assistance of bioinformatic tools. We used 5 identified immune checkpoints (CTLA4, LAG3, TIM3, TIGIT and BTLA) as templates for potential immune checkpoints screening by application of the GEPIA2 and TCGA datasets. The druggability of potential checkpoints we revealed in this paper (ICOS, CXCR6, SIRPG, FASLG and SLAMF6) are assessed by survival and stage analysis, which also come from GEPIA2. These genes are not only associated with the prognosis and survival of cancer but also varied expression across different stages of particular cancer, such as SKCM and LUAD. This suggests that these genes could be drug targets and drugs developed against them may be is an agonist. However, the basic biology and pre-clinical studies of these genes only partially agree with our results. The anti-ICOS and CXCR6 therapy could use agonist drugs, however, the current treatment design for targeting SIRPG, FASLG and SLAMF6 depends on their inhibition. This suggests that our result require further experiment to assess the signalling of these genes in cancer and solid tumour conditions for optimisation, and our identification strategy is worked.