The immune system is an extremely complicated system that is continuously evolving to maintain homeostasis. The intact immune responses, such as immune surveillance or immunoediting are mandatory for maintaining intrinsic physiological functions of the immune system. The fundamental characteristics that enable immune cells to perform efficient immune surveillance include Integrin-mediated adhesion, antigen recognition, activation, and motility. However, a slight discrepancy in these fundamental characteristics or their components leads to a pathological condition. Autoimmune disorders, chronic inflammation, and tumor evasion are the manifestations of extravagant T-cell responses 3. Chronic inflammation is a critical hallmark of cancer. Various studies support that the diverse immune cells infiltration plays a central role in smoldering inflammation in the tumor microenvironment. The dynamic tumor-immune cell interplay gives rise to excessive production of chemokines and growth factors that are not only encouraging tumor growth but also help in tumor cell evasion from its primary site 158,204. Similarly, autoimmune disorder studies have shown enhanced embracement of migratory attributes by immune cells in some cases. Chemokines and chemokine receptors upregulation in blood and cerebrospinal fluid of MS patients is a well-known phenomenon 76,77. Further, overexpression of adhesion molecule responsible for enhanced macrophage migration and activation in active SLE patients, which is associated with its uncontrolled tissue recruitment and excessive inflammatory cytokine production 52. Collectively, excessive T-cell activation and migration are related to autoimmune diseases, chronic inflammation, and tumor evasion. In the case of multiple inflammatory disorders, extravagant tissue infiltration of immune cells leads to significant pathogenesis, hence pharmacological inhibition of immune cell motility can be of prime therapeutic value. There are inadequate target-specific and potent therapies available against the chronicity of such diseases. Eventually, immunosuppressants including corticosteroids are used for the long term but they are also associated with potential adverse effects. Thus, a definitive targeted therapy is required that can control actin-based immune cell responses for the regulation of autoimmune diseases and tumor progression. Ena/VASP proteins are key actin regulators and their EVH1 domain is responsible for the localization of actin machinery within the cells.
A small-molecule inhibitor targeting the Ena/VASP-EVH1 domain has been designed in order to inhibit the proline-mediated protein-protein interactions. EVH1 inhibitor data in Jurkat cells and macrophages interpreted that by targeting the EVH1 domain of Ena/VASP, actin-rich structure lamellipodia formation is hindered, and therefore migration is interrupted. Moreover, the EVH1 inhibitors have shown a significant reduction in effective antigen recognition in T cells. Thus, based on our findings, I concluded that inhibition of the EVH1 domain by a small molecular inhibitor can be a promising approach to regulate immune cell responses. Jurkat cells data provide a promising starting point for the characterization of EVH1 inhibitors in in-vivo models as a promising therapy for various autoimmune diseases and metastasis. However, EVH1 inhibitors need modification to enhance their cell permeation, which ultimately increases the bioavailability and efficiency.
Furthermore, the importance of WAVE2 and ADAP in T-cells actin cytoskeletal related processes was unveiled. These are two important interaction partners of the EVH1 domain in T-cells that are displaced by EVH1 inhibitors. WAVE2 is an actin regulatory protein, and ADAP is an immune cell-specific adaptor protein that mainly regulates immune-specific functions. Here, we found that in Jurkat cells, WAVE2-EVH1 interaction is necessary for lamellipodia formation, cell spreading, and migration. Whereas ADAP with Ena/VASP direct link is necessary for the formation of immune synapsis. In conclusion, the Ena/VASP-EVH1 mediated interaction of both proteins holds an important place in T-cell functionality.