Targeting T Cells

T Cell Dysfunction

T cells can take part in a variety of immune responses in cancer. Among them, cytotoxic CD8⁺ T cells (CTLs) are a major population of immune cells that control and clear tumor cells. However, due to persistent antigen exposure and the immunosuppressive TME, the function of T cells becomes compromised, termed T cell dysfunction. Immune inhibition renders T cells dysfunctional in the tumor microenvironment (TME). T cell anergy, exhaustion, and senescence are all considered different types of T cell dysfunction.

• T cell anergy is an inactive state in which T cells produce low levels of IL-2 resulting in incomplete effector T cell differentiation.
• T cell exhaustion is representative of T cell dysfunction. Exhausted T-cells demonstrate impaired effector functions including reduced cytotoxicity and cytokine secretion, impaired proliferation, reduced responses to cytokine stimulation, upregulation of inhibitory checkpoint receptors, and may ultimately undergo apoptosis. Most T cells in the TME are exhausted, leading to cancer immune evasion.
• T cell senescence is characterized by decreased CD28 expression, thus preventing T cell costimulation, leading to the loss of genes at chromosomal ends and subsequently the cessation of the cell cycle.

Fig.1 Classification of dysfunctional T cells.^1,3

Treg Cells and Immune Inhibition

In the TME, cancer cells achieve immunosuppression through the recruitment of immunosuppressive cells (regulatory T cells (Treg) and myeloid-derived suppressor cells) and the expression of ligands for coinhibitory checkpoint molecules such as programmed death-1 (PD-1). Treg cells are considered immunosuppressive cells of the TME. High Treg cell infiltration in the TME is involved in unfavorable prognosis in patients with various types of cancer. Mechanisms of suppression by Treg include cell contact-dependent mechanism and independent mechanism. Contact-dependent mechanisms include interactions between cognate receptors and ligands such as CTLA-4:CD80/CD86, LAG-3:MHC II, and Nrp-1:MHC II. Interactions of these can result in impairing the maturation of dendritic cells (DCs) and inhibiting activation, proliferation, cytokine production, and survival pathways of effector T cells through interactions with antigen-presenting cells. In addition, Tregs also employ contact independent mechanisms of suppression mediated through the secretion of inhibitory cytokines and local competition for growth factors. Therefore, depletion of Treg cells or the control of Treg cell functions could be promising immunotherapies.

Cell-based Immunotherapy

The immunosuppressive TME has implications for T cell function in terms of differentiation and exhaustion. The presence of T cells in TME correlates with favorable treatment and prognosis. With the rapid development of immunotherapy, enhancing T cell function is a promising strategy in antitumor immunotherapy and reverse immunosuppressive TME. A sufficient infiltration into the TME and successful activation of effector T lymphocytes against tumor cells have been identified as predictors for responses to T cell-based immunotherapies.

• Reduction T cell inhibition. T cell-inhibitory mechanisms are often dominant in the TME. It is possible that therapy success is achieved by therapeutic reduction of T cell inhibition, for example, by targeting inhibitory receptors, unfavorable metabolites, IDO, arginase 1, M2-like macrophages, MDSCs, or Treg cells.
• Increasing T cell activation. Targeting genes with more specific expression and effects on T cell dysfunction or inappropriate cell polarization, such as MAF, FOXP1, or STAT3, may be more promising, potentially allowing specific correction of dysregulated mechanisms in cancer-specific T cells.
• Adoptive cell transfer. Adoptive cell therapy with autologous T cells offers the possibility of genetic modification of T cells before they are infused back into the patient. Adoptive T cell therapy represents a unique and innovative therapeutic pillar for cancer treatment. Chimeric antigen receptor T cells therapy (CAR-T) and T cell receptor (TCR)-T cell therapy are the latest and most effective immunotherapy technologies.
• Vaccines. In vivo DCs-targeted vaccines that deliver tumor antigens to cross-presenting DCs with monoclonal antibodies carrying tumor antigens are another attractive approach to enhance the cross-priming of tumor-specific CD8 T cells.

Fig.2 Overview of basic principles of tumor-specific immune activation and the involved cell type.^2,3

Our Services

Creative Biolabs provides a series of one-stop targeting T cell services, including but not limited to:

• One-Stop CAR-T Therapy Development Services
• One-Stop TCR-T Therapy Development Services
• Bispecific TCR & TCR-Like Antibody Services
• DCs Vaccines

Creative Biolabs has developed a range of services by targeting T cells to reshape TME. Our scientists are always ready to help you accelerate your cutting-edge immune-modulating therapies. Please feel free to contact us to learn how we can be involved in your project.

References

1. Xia, Anliang, et al. "T cell dysfunction in cancer immunity and immunotherapy." Frontiers in immunology 10 (2019): 1719.
2. Mohme, Malte, and Marian Christoph Neidert. "Tumor-specific T cell activation in malignant brain tumors." Frontiers in immunology 11 (2020): 205.
3. Distributed under Open Access license CC BY 4.0, without modification.