Table 2.

Immune checkpoint proteins in patients with LC-TB

Target	Biological functions	Expression position	Effector cells	Route of action	Mechanism of action	Significance
Programmed death receptor 1 (PD-1)	Co-inhibitory receptors	Activated T and B cells and myeloid cells138	PD-L1 on the surface of T cells, B cells, dendritic cells and macrophages, and tumor cells1139	PD-1 and PD-L1 binding pathway	In the LC microenvironment, the interaction between the heightened expression of PD-L1 and PD-1 obstructs the activation of T-cells,140 while simultaneously promoting the differentiation and proliferation of Tregs.144	By inducing T cell exhaustion, the evasive mechanism of tumor cells or MTB-infected cells from the host immune system’s surveillance and clearance is facilitated, subsequently fostering the progression and manifestation of diseases.
Cytotoxic T lymphocyte antigen 4 (CTLA-4)	Co-inhibitory receptors	Lym T phosphate cells149	CD80/CD86 on the surface of antigen-presenting cells or tumor cells150	CTLA4 binding pathway to CD80/CD86	CTLA4 demonstrates a competitive and high-affinity binding to CD80/CD86 on antigen-presenting cells or tumor cells, consequently impeding the activation signal transmitted through the interaction of TCR and CD28. This ultimately results in the suppression of T cell activity.149,150,151	The induction of T cell exhaustion enables the evasion of tumor cells or MTB-infected cells from the surveillance and clearance mechanisms of the host immune system. This evasion subsequently promotes the occurrence and progression of diseases.
Lymphocyte Activating Gene 3 (LAG-3)	Co-inhibitory receptors	Activated CD4+ and CD8+ T cells154	MHC class II molecules presented by antigen-presenting cells156	LAG-3 and MHCII binding pathway	The initial domain of LAG-3 exhibits greater activity compared to CD4, and it selectively binds to MHC II, leading to a reduction in T cell proliferation and cytokine secretion.156	Inducing T cell exhaustion can enable evasion of the surveillance and clearance of tumor cells or MTB-infected cells by the host immune system, thus promoting the occurrence and development of diseases.
T cell immunoglobulin structural domain and mucin structural domain 3 (TIM-3)	Co-inhibitory receptors	monocytes (highest expression in dendritic cells), Th1-type cells164	Binding of galactose lectin-9 (galectin-9) expressed on the surface of tumor cells165	The binding pathway of TIM-3 with galectin-9.	The binding of TIM-3 with galectin-9 on the surface of tumor cells leads to the death of Th1-type T cells, resulting in a decrease in their secretion of the cytokine IFN-γ.164,165	Inducing T cell exhaustion can evade the surveillance and clearance of tumor cells or MTB-infected cells by the host immune system, thus promoting the occurrence and development of diseases.
Glucocorticoid-induced TNF receptor (GITR)	Co-stimulatory receptors	Activation of T cells induces the upregulation of expression in different cells and tissues.167,172	GITRL on the surface of antigen-presenting or tumor cells.190	The binding pathway of GITR with GITRL.	The binding of GITR with GITRL on the surface of APCs can increase T lymphocyte proliferation and cytokine production, as well as promote the differentiation and expansion of Th17 cells and Tfh.167,172,174 When binding with GITRL in the tumor microenvironment, it inhibits the suppressive function of Tregs.190	Enhancing T cell immune function can boost the longevity of inflammatory cytokines and strengthen the adaptive immune response mediated by T cells in the body.

LC, Lung cancer; TCR,T cell receptor; APCs, antigen-presenting cells; Tfh, T follicular helper cells.