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. 2023 Jan 12;24(2):1506. doi: 10.3390/ijms24021506

Table 4.

Immune checkpoints considered in lung cancer research.

Pathway Molecules Found on Cancer Cells Molecules Found on T Lymphocytes
Name Gene and Location Amino Acid Length and Molecular Weight Function Name Gene and Location Amino acid Length and Molecular Weight Function References
Inhibitory pathway A2aR ADORA2A,
22q11.23		 412 aa;
44.707 kDa

  • Plays a regulatory role in the adaptive immune system;

  • Extracellular adenosine binds to the receptor, causing a G protein-coupled response, resulting in upregulation of TGF-β and PD-1;

  • Interactions with FOXP3 stimulate CD4+ T cells further suppressing the immune response.

 No data [362,363,364,365]
VISTA C10orf54,
10q22.1		 311 aa,
33.908 kDa

  • Belongs to the B7 family;

  • Its transcription is partially controlled by p53;

  • Produced in large amounts in tumor-infiltrating lymphocytes, such as myeloid-derived suppressor cells and regulatory T cells.

 No data [364,366,367]
B7-H3 CD276, 15q24.1 534 aa, 57.235 kDa

  • In benign tissues, it mainly plays an inhibitory role in adaptive immunity by inhibiting T-cell activation and proliferation;

  • In malignant tissues, it inhibits immune responses specific to the tumor antigen;

  • Has non-immune prone-forming functions, such as promotion of migration, invasion, angiogenesis and chemoresistance.

 No data [368,369,370,371]
PD-L1 CD274, 9p24.1 290 aa, 33.275 kDa

  • Plays a major role in suppressing the adaptive response of the immune system;

  • The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via the immunoreceptor tyrosine switching motif (ITSM).

  • It reduces proliferation of antigen-specific T cells in lymph nodes while reducing apoptosis in regulatory T cells.

 PD-1 PDCD1,
2q37.3		 288 aa,
31.647 kDa

  • Protein on the surface of T and B lymphocytes that plays a role in regulating the immune response and promoting self-tolerance by suppressing the inflammatory activity of T lymphocytes;

  • It prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

 [346,372,373,374,375,376,377,378]
PD-L2 PDCD1LG2, 9p24.1 273, 30,957
CD80 CD80, 13q13.3-q21 288 aa, 33.048 kDa

  • Can be expressed on antigen presenting cells (APCs) or tumor cells;

  • Interacts with both co-stimulatory (CD28) and coinhibitory receptors (cytotoxic T lymphocytes, antigen 4 (CTLA-4)) and regulates the immune response;

  • The low level of CD80 expression serves as a tumor escape mechanism due to the higher affinity and therefore preferential binding of CTLA-4 to CD80 compared to CD28;

  • In contrast, CD80 overexpression promotes T cell activation and tumor rejection, and CD80 deficiency also increases the immunogenicity of tumor cells.

 CTLA-4 CTLA-4, 2q33.2 223 aa,
24.656 kDa

  • Expressed by activated T cells and transmits an inhibitory signal to T cells;

  • CTLA4 expression has been found in many cancers, including non-small-cell lung cancer (NSCLC) tissues and cells; its function in cancer cells is unknown.

 [379,380,381,382,383,384,385,386]
CD86 CD86, 3q21 323 aa, 37.021 kDa

  • Acts in parallel with CD80 (B7-1) as a natural ligand for CD28 and CTLA-4;

  • Promotes T-cell proliferation, function and survival by interacting with CD28 as a co-stimulator, while in activated T cells it interacts with CTLA-4 and acts as a suppressor.
Galectin 9 LGALS9, 17q11.2 355 aa,
39.518 kDa

  • HAVCR2/galectin-9 interaction attenuated T-cell expansion and effector function in the tumor microenvironment and chronic infections;

  • Contributes to the formation of tumors through the transformation of cancer cells, regulation of the cell cycle, angiogenesis and cell adhesion.

 TIM3 HAVCR2,
5q33.3, 		301 aa,
33.394 kDa

  • Belongs to the cell surface receptor proteins of the TIM family;

  • Transmembrane protein of T lymphocytes (CD4+ and CD8+ T cells), myeloid cells (monocytes, macrophages, DCs, mast cells, NK cells) or various cells in various types of cancers;

  • Mediates depletion of CD8+ T cells for proliferation and secretion of cytokines such as TNF-alpha, IFN-gamma and IL-2.

 [387,388,389,390,391,392]
HVEM TNFRSF14, 1p36.32 283 aa,
30.392 kDa

  • Belongs to the superfamily of TNF receptors;

  • Cytoplasmic region of this receptor binds to several members of the TNF receptor-associated factor (TRAF) family, which may mediate signal transduction pathways that activate the immune response;

  • HVEM overexpression in NSCLC patients was significant in patients with N2 lymph node metastases;

  • Shows a negative correlation with PD-L1 expression in NSCLC patients.

 BTLA BTLA, 3q13.2 289 aa,
32.834 kDa

  • Expressed in lymph nodes, thymus and spleen;

  • Through ITIM, it recruits SHP-1 or SHP-2, which act as phosphatases and dephosphorylate tyrosine, which inhibits immune activation;

  • Has a Grb-2 recognition motif which, when recognized by the Grb-2 protein, promotes PI3K activation and additionally mediates cell proliferation and survival;

  • High BTLA expression may predict poor prognosis in NSCLC patients.

 [393,394,395,396,397]
MHC II HLA-DP, -DQ and –DR, chromosome 6 -

  • A complex of proteins responsible for the presentation of antigens to T lymphocytes;

  • Correlates with the prognosis of patients with neoplastic diseases and is important in the selection of patients for immunotherapy.

 LAG3 LAG3, 12p13.31 525 aa,57.449 kDa

  • Expressed on activated T and B cells, NK cells, and plasmacytoid dendritic cells;

  • Binds to MHC class II with greater affinity than CD4.

  • Negatively regulates cell proliferation, activation and homeostasis of T cells in a similar way to CTLA-4 and PD-1.

 [398,399,400,401,402]
Stimulatory pathway OX40L TNFSF4, 1q25.1 183 aa,
21.050 kDa

  • Expressed on DC2, macrophages and activated B cells;

  • OX40-OX40L ligation is a source of survival signal for T cells and enables the development of memory T cells;

  • Signaling by these two molecules also polarizes towards a Th2 immune response, even in an environment with low levels of the cytokine IL-4.

 OX40 TNFRSF4, 1p36.33 277 aa,
29.341 kDa

  • Present on the surface of activated T cells (mainly CD4+ T cells), but also on NK cells, NKT cells and neutrophils;

  • OX40 plays a key role in NSCLC and SCLC.

 [403,404,405,406]
CD40 TNFRSF5, 20q12-q13.2 117 aa,13.158 kDa

  • Protein found on the surface of antigen-presenting cells, necessary for their activation and providing a co-stimulatory signal to T cells expressing the CD154 molecule;

  • Binding of CD154 to CD40 triggers signaling pathways based on TRAF proteins.

 CD40L CD40LG, Xq26 261 aa,
29.274 kDa

  • Protein found primarily on T lymphocytes, belonging to the TNF superfamily.

  • Its main function is to bind the CD40 molecule on antigen-presenting cells and deliver the co-stimulatory signal required for lymphocyte activation.

 [407,408,409,410]
B7RP1 ICOSG, 21q22.3 302 aa,
33.349 kDa

  • Belongs to the B7 family of co-stimulatory ligands;

  • Shares 19–20% sequence identity with CD80 and CD86;

  • Causes activation and proliferation of T cells;

  • The ICOS/ICOSLG axis promotes antitumor T-cell responses (when activated in Th1 and other Teffs) or protumor responses when triggered in Tregs.

 ICOS ICOS, 2q33.2 199 aa,
22.625 kDa

  • Costimulatory molecule of the CD28 superfamily that is expressed on activated T cells.

 [411,412,413,414,415]
CD70 CD70, 19p13.3 193 aa,
21.118 kDa

  • Belongs to the tumor necrosis factor (TNF) family of ligands;

  • Surface antigen on activated but not resting T and B lymphocytes;

  • Responsible for inducing the proliferation of co-stimulated T cells, increasing the production of cytolytic T cells and contributes to the activation of T cells.

 CD27 CD27,
12p13.31		 260 aa,
29.137 kDa

  • Necessary for the production and long-term maintenance of T-lymphocyte immunity;

  • Its binding to CD70 activates the signaling cascade leading to differentiation and clonal expansion of T cells;

  • Results in improved survival and memory of cytotoxic T cells and increased production of some cytokines;

  • Transmits signals that lead to the activation of NF-κB and MAPK8 / JNK

 [416,417,418,419,420,421]
GITRL TNFSF18, 1q25.1 177 aa,
20.308 kDa

  • Regulates T cell responses;

  • May act as a co-stimulator and lower the threshold for T cell activation and T cell proliferation

  • Important for the interaction between activated T cells and endothelial cells;

  • Mediates the activation of NF-kappa-B.

 GITR TNFRSF18, 1p36.33 241 aa,
26.000 kDa

  • Constitutively expressed on CD25+ CD4+ regulatory T cells and is upregulated in all subsets of T cells upon activation;

  • Signaling may promote anticancer and anti-infective immune responses, but may also be a driver of autoimmune diseases.

 [422,423,424,425]
4-1 BBL TNFSF9, 19p13.3 254 aa, 26.625 kDa

  • Interaction between 4-1BB and 4-1BBL provides co-stimulating signals for various T cells that can be used to discover cancer immunotherapy.

 4-1 BB TNFRSF9, 1p36.23 255 aa,
27.899 kDa

  • Expressed by activated T cells of both CD4+ and CD8+ lines;

  • Increased T cell proliferation, IL-2 secretion, survival and cytolytic activity.

 [426,427,428,429,430]
CD155 PVR, 19q13.31 417 aa,
45.303 k Da

  • Type I transmembrane glycoprotein of the immunoglobulin superfamily;

  • Commonly known as the poliovirus receptor (PVR);

  • It mediates NK cell adhesion and triggers NK cell effector functions

 TIGIT TIGIT, 3q13.31 244 aa,
26.319 kDa

  • Binding to CD155 results in increased secretion of IL10 and decreased secretion of IL12B and inhibition of T cell activation by promoting the production of mature immunoregulatory dendritic cells

 [431,432,433,434]

Abbreviations: A2aR—adenosine A2A receptor; VISTA—V-domain Ig suppressor of T-cell activation; B7-H3—B7 homolog 3 protein; PD-1—programmed death receptor-1; PD-L1—programmed death-ligand 1; PD-L2—programmed death-ligand 2; CD80—cluster of differentiation 80; CD86—cluster of differentiation 86; TIM-3—T-cell immunoglobulin mucin-3; HVEM—herpes virus entry mediator; BTLA—B and T lymphocyte attenuator; MHC—major histocompatibility complex; LAG3—lymphocyte activating 3; OX40L—OX40 ligand; CD40—cluster of differentiation 40; CD40L—cluster of differentiation 40 ligand; ICOSLG—inducible T-cell costimulator ligand; ICOS (B7RP-1)—inducible T-Cell costimulator; CD70—cluster of differentiation 70; CD27—cluster of differentiation 27; GITR—glucocorticoid-induced tumor necrosis factor receptor-related protein; GITRL—glucocorticoid-induced tumor necrosis factor ligand-related protein; CD155—cluster of differentiation 155; TIGIT—T-cell immunoreceptor with Ig and ITIM domains.