Milad Sabzevary-Ghahfarokhi Faculty of Medicine Shahrekord University of Medical Sciences
Hedayatollah Shirzad Shahrekord University of Medical Sciences
Mahmoud Rafieian-Kopae Shahrekord University of Medical Sciences
Mahdi Ghatreh-Samani Shahrekord University of Medical Sciences
Mojtaba Shohan Faculty of Medicine Shahrekord University of Medical Sciences

Potential Approaches for Improving Antitumor Activity of T Cells and Intervention into T Cell Exhaustion

The immune system recognizes cancerous cells by screening the tumor antigen during malignant progression. By producing cytokines, the cells of the immune system have the ability to arrest division and migration of cancer cells.1 Cancer cells commonly change the cytokine profile so that the innate and adaptive immune cells are differentiated in the tumor microenvironment.2,3 Cytotoxic T lymphocytes (CTL), which are exposed to the microenvironment in tumor tissues and peripheral blood, lose their antitumor activity and express inhibitor marker on their surface. In fact, these lymphocytes are transformed to exhausted T cells with different features in phenotype and performance.2

Investigations have shown that the exhausted T cells give rise to resistance against chemotherapy and develop angiogenesis by interleukin (IL)-8 and IL-6 production.4,5 The limitations in specific antigen diagnosis and T cell activation have led to the limitation of using novel immunotherapy techniques, such as chimeric antigen receptor (CAR) and T cell receptor (TCR) transgenic T cells.6,7 Recently, some immune checkpoint inhibitors, such as ipilimumab, act against inhibitor markers and have replaced chemotherapy and radiotherapy in melanoma and some sorts of leukemia. Although these antibodies seem to be effective drugs to activate exhausted T cells, they create systemic complications, such as diarrhea in the gastrointestinal tract, rash, pancreatitis, and autoimmune diseases.8,9

Further investigations on tumor microenvironments in different kinds of cancer can improve insights on immune system change in this condition. In this article, the authors reviewed the phenotypes and function of exhausted T cells and described the expression pattern of inflammatory cytokines in tumor tissues and peripheral blood of cancer patients. The effects of inflammatory cytokines on intracellular factors and signals are identified to clarify the inactivation state. Likewise, exhausted T cells in some kinds of chronic inflammatory diseases, which have similar immunological characters, were considered.

The Exhausted T Cells and Their Markers

Exhausted T cells are capable of eliminating cancer cells; however, they enter an inactive state due to their presence in the microenvironment in various infections, autoimmune diseases, and cancer. These lymphocytes receive combined signals after raised inhibitory markers, including PD-1 (programmed cell death-1), Tim-3 (T cell immunoglobulin mucin-3), LAG-3 (lymphocyte activation gene-3), and TIGIT (T immune receptor with Ig and ITIM domain). However, the loss of activator markers, such as (CD127)IL-7R, CD28, CD27, and IL-15R extensively decrease the function of exhausted T cells in response to external signals. Exhausted T cells are not able to mobilize and release granules, including IFN-γ and granzyme β that have dramatically been assembled in the lymphocytes.10,11 The differentiation and the most significant features of exhausted T cells are shown in Figure 1.

Oxidative phosphorylation, which is the central pathway for effector T cells to receive energy, is modulated in exhausted T cells. Alternatively, glut1 is significantly expressed in the exhausted T cells leading to elevated glycolysis pathway12,13 T cell exhaustion enriched in the tumor microenvironment are termed “Tumor-induced senescent T,” because they are similar to lymphocytes in older people. Senescent T lymphocytes face oxidative stress and inflammation conditions created by M2 macrophages and dendritic cells. These cells usually induce angiogenesis factors and have short length of telomeres and blunt cell cycle.3,14

Programmed cell death-1

Surface cell marker PD-1 (CD279) is a member of the immunoglobulin CD28 superfamily, which have the potential to regulate the function of effector T cells. PD-1 intracellular domain transfers inhibitory signals that affect cell functions. PD-1 binds to PD-1L (B7-H1) found on cancer cells and antigen-presenting cells and PD-2L (B7-H2) on cancer cells, respectively. This immunoreceptor contains tyrosine-based inhibitory motif (ITIM) that recruits Src homology region two domain-containing phosphatase-1 (SHP-1), SHP-2, and SH2-domain-containing phosphatidylinositol 5-phosphatase. Phosphatase signals are then created when the immunoreceptor engages with a ligand. This signal represses the function of serine–threonine kinase Akt and phosphoinositide 3-kinase, which sustains retinoblastoma factor dephosphorylation. On the other hand, mammalian cyclin-dependent kinase inhibitor remains stable against the effects of UbQ ligase-SCF, and consequently, the cell cycle of T cells is stopped.15,16 The downstream signal of PD-1 motivates basic leucine zipper transcription factor ATF-like (BATF) by which PD-1 expression is induced through a positive feedback.17 In T cell exhaustion, pd-1 gene promoter (pdcd1) remains demethylated in contrast to the other T lymphocytes. This state is coupled with high amounts of transcription factors, such as NFAT, STAT3, BLIMP, and EOMES, which directly control different areas of the pdcd1 to be active.9,18 Conversely, transcription factor T-bet is downregulated in patients suffering from cancer. T-bet further modulates PD-1 expression. As a result, all these conditions help to promote PD-1 expression.19,20 Investigations on colorectal cancer in experimental mice treated by MAPK inhibitor and injected anti-PD-1L antibodies showed that the T-bet of CD8+ T cells increased while tumor size decreased. Although MAPK is very important for IL-2 production and cell activation in naive T cells, a continuous exposure to antigen by lymphocyte's TCR results in encoding nur77 gene and CTL apoptosis.21 A fraction of NY-ESO-1-specific CD8+ T cells in patients with advanced melanoma expressed PD-1, Tim-3, and LAG-3 simultaneously. It offered the possibility that NY-ESO-1-specific T cells upon prolonged antigen stimulation, along with the interaction of PD-1 and ligand, resulted in upregulation of the inhibitor marker expression.22

T cell immunoglobulin mucin-3

This marker can activate intracellular attenuation of T cells in response to galectin-9. This connection triggers inhibitor signals in addition to releasing an influx of Ca2+ into the lymphocytes, and thus induces apoptosis. The coexpression of PD-1 and Tim-3 has been reported in some kinds of cancers and virus infections.23 Simultaneous injection of anti-PD-1 and anti-Tim-3 antibody in a mice model of breast, colorectal, and melanoma tumor produced more of the IFN-γ, which eventually controlled tumor growth. The prescription of anti-PD-1 alone for lung cancer patients resulted in increasing Tim-3 expression.24,25 Tim-3 intracellular domain links to HLA-Bat3 (B-associated transcript 3) in playing a pivotal role in the proliferation and production of inflammatory cytokines.26 Tim-3 intracellular signal in dendritic cells arrests HMGB1 pathway by which DNA antigens are recognized through TLR-4. Therefore, the efforts of the innate immune system against a cancerous mass would be in vain.27

P-selectin glycoprotein ligand 1

P-selectin glycoprotein ligand 1 (PSGL-1) is a mucin-like glycoprotein observed on the surface of myeloid, lymphocyte, and endothelial cells. Psgl-1 binds to lymph node homing molecules, such as L-selectin. Conversely, it can also join to P and E-selectin related to cadherin, which facilitates lymphocyte movement into inflammatory regions.28 Likewise, CCL-19 and CCL-21 chemokines are capable of interacting with Psgl-1 on the memory and naive T cells to trigger inhibitor signal into cells. Psgl-1 correlates PD-1 expression on the CD8+ T cells in melanoma mice and LCMV-C13-infected mice. Eliminating psgl-1gene in CD8+ T cells leads to the elevation of T-bet, IL-2/7/15R, and reduction of PD-1 and Tim-3.29,30 ERM (EZRIN/RADIXN/MOESIN) covers other markers of immunoreceptor tyrosine-based activation motif (ITAM) and interacts with the Psgl-1 intracellular domain. Accordingly, ITAM domain is not detected by Syk in the presence of Psgl-1 signals. ERM, along with Csk-binding protein (Cbp), activates c-Src associated with EBP50 protein. c-Src prohibits the formation of a mature immunological synapse to respond to phosphorylating lymphocyte-specific protein tyrosine kinase (Lck) in T cells.31,32

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Cancer Biotherapy and Radiopharmaceuticals, published by Mary Ann Liebert, Inc., provides peer-reviewed research on cutting-edge therapeutic investigations and advancements in radioimmunotherapy for treating cancer. The above article was first published in the August, 2018 issue of Cancer Biotherapy and Radiopharmaceuticals with the title “The Role of Inflammatory Cytokines in Creating T Cell Exhaustion in Cancer". The views expressed here are those of the authors and are not necessarily those of Cancer Biotherapy and Radiopharmaceuticals, Mary Ann Liebert, Inc., publishers, or their affiliates. No endorsement of any entity or technology is implied.

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