The Proliferative Role of Immune Checkpoints in Tumors: Double Regulation

Abstract

Cancer remains a serious social health problem, and immunotherapy has become the major treatments in tumor treatment. Additionally, improving the efficiency and safety of treatment is necessary. Further, more therapy targets are warranted for future tumor treatments. In this review, in addition to examining the currently recognized role of immune regulation, we focus on the proliferative role of 15 immune checkpoints in various tumors, including PD1, PD-L1, FGL1, CD155, CD47, SIRPα, CD276, IDO1, SIGLEC-15, TIM3, Galectin-9, CD70, CD27, 4-1BBL, and HVEM. We managed to conclude that various immune checkpoints such as PD1/PD-L1, FGL1, CD155, CD47/SIRPα, CD276, and SIGLEC-15 all regulate the cell cycle, and specifically through Cyclin D1 regulation. Furthermore, a variety of signal pathways engage in proliferation regulation, such as P13K, AKT, mTOR, and NK-κB, which are also the most common pathways involved in the regulation of immune checkpoint proliferation. Currently, only PD1/PD-L1, CD47/SIRPα, TIM3/Galectin-9, and CD70/CD27 checkpoints have been shown to interact with each other to regulate tumor proliferation in pairs. However, for other immune checkpoints, the role of their receptors or ligands in tumor proliferation regulation is still unknown, and we consider the enormous potential in this area. An increasing number of studies have validated the various role of immune checkpoints in tumors, and based on this literature review, we found that most of the immune checkpoints play a dual regulatory role in immunity and proliferation. Therefore, the related pathways in proliferation regulation can served the role of therapy targets in tumor therapy. Further, great potential is displayed by IDO1, SIGLEC-15, 4-1BBL, and HVEM in tumor proliferation regulation, which may become novel therapy targets in tumor treatment.

Galectin-9 in cancer therapy: from immune checkpoint ligand to promising therapeutic target

“…We believe that Gal-9’s ability to counteract tumor cell evasion from immune surveillance may be influenced by tumor heterogeneity and its varying benefits for immunotherapy. Interestingly, studies on “unlimited proliferation” and “apoptosis”, also tumor hallmarks, have found that these two “hallmarks” are concentrated in gastrointestinal tumors ( Tang et al, 2022 ), including colorectal cancers ( Sasidharan Nair et al, 2018 ; Blair et al, 2021 ), EAC ( Akashi et al, 2017 ), ESCC ( Chiyo et al, 2019 ), gallbladder ( Tadokoro et al, 2016 ), and bile duct ( Kobayashi et al, 2015 ).…”

A Comprehensive Pan-cancer Analysis of the Biological Immunomodulatory Function and Clinical Value of CD27

“…These show that the CD27 has a dual role in the progression of certain cancers 42 . The study of Ortiz-Cuaran et al demonstrated that CD27L is highly expressed in non-small cell lung cancer and predicts reduced infiltration of CD8 + T cells as well as immune depletion 43 , 44 . At the same time, CAR-T therapy targeting CD27L has also become a new role in cancer treatment 45 , 46 .…”

Investigating the immune mechanism of natural products in the treatment of lung cancer

“…Preliminary inquiries have revealed the presence of specific immunosuppressive metabolites expressed on effector T cells, which function to inhibit excessive activation of T cells and the resulting emergence of autoimmune conditions. As a result, widespread attention has been attracted to the role of these molecules in regulating immune balance ( Tang et al, 2022b ). Additional examination has revealed more information regarding the increased presence of these checkpoint molecules in circumstances like cancerous growths, persistent viral infections, and bacterial infections within immune cells.…”