Role of T cells in cancer immunotherapy: Opportunities and challenges

Abstract

Immunotherapies boosting the immune system's ability to target cancer cells are promising for the treatment of various tumor types, yet clinical responses differ among patients and cancers. Recently, there has been increasing interest in novel cancer immunotherapy practices aimed at triggering T cell-mediated anti-tumor responses. Antigen-directed cytotoxicity mediated by T lymphocytes has become a central focal point in the battle against cancer utilizing the immune system. The molecular and cellular mechanisms involved in the actions of T lymphocytes have directed new therapeutic approaches in cancer immunotherapy, including checkpoint blockade, adoptive and chimeric antigen receptor (CAR) T cell therapy, and cancer vaccinology. This review addresses all the strategies targeting tumor pathogenesis, including metabolic pathways, to evaluate the clinical significance of current and future immunotherapies for patients with cancer, which are further engaged in T cell activation, differentiation, and response against tumors.

Keywords: Cancer; Immune system; Immunotherapy; Metabolic pathways; T cell.

Graphical abstract

Figure 1

Action of a potential CD4+ T cell-based immunotherapy strategy against cancer. CD4+ T cells have a vital role in cancer and cancer immunotherapy. Immune checkpoint inhibitors are a potential strategy for cancer cells to bypass immune cell attacks. CD4+ T cells can be primed through therapeutic vaccination via generalized or personalized vaccines. These are designed according to patients' white blood and particular cancer cells. Blood is collected and reprogrammed through adoptive cell therapy and individual CAR T cell therapy. This cell therapy can mediate more specific attacks against cancer cell lines in CD4+ T cells. CAR genes are introduced into CD4+ T cell lines and amplified. Reprogrammed CAR T cells are administered into the patient's blood. In adoptive cell therapy, engineered CD4+ T cell lines are activated via cancer or antigen-presenting cells to increase the immune response. CAR: Chimeric antigen receptor.

Figure 2

Action of CD8+ T cells in cancer.CD8+ T cells, or CTLs, are frontline immune cells employed in cancer and cancer immunotherapy. They kill potentially harmful cells in the body, including tumor/tumor-like cells, viruses, and foreign antigens. The activation and proliferation of CD4+ T cells and their interaction with APCs result in IL-22 release. IFN-γ helps naïve CD8+ T cells to convert to mature CD8+ T cells. Effector CD8+ T cells are produced from mature CD8+ T cells and are short-lived. They can kill tumors or tumor-like cells either directly or indirectly. (A) Direct CTL-mediated killing via perforin and granzyme. This necessitates a cell-to-cell interaction, accompanied by the release of cytolytic enzymes, such as granzyme B. Perforin released by CTL creates pores in a juxtaposed cancer cell membrane, enabling passive inward diffusion of granzyme B. This causes the targeted cells to undergo apoptosis. (B) Direct tumor cell killing can occur due to an association between the Fas-L, expressed by CTL, and its receptor, Fas, represented by cancer cells. Fas/Fas-L ligation induces cancer cell apoptosis through a caspase-dependent pathway. (C) Indirect CD8+ T cell-mediated killing: CTLs can cause indirect or “bystander” tumor cell death by secreting cytokines that act at a distance. TNF-α secretion can trigger apoptosis in tumor cells that express the TNF receptor. APCs: Antigen-presenting cells; CTLs: Cytotoxic T lymphocytes; Fas-L: Fas ligand; IFN-γ: Interferon-γ; IL: Interleukin; TNF: Tumor necrosis factor.

Figure 3

Schematic presentation of CD8+ T cell population in cancer immunotherapy. Mature CD8+ T cells are subdivided into three groups based on their use and activity: Tcm, Tem, and Teff. These cells have essential and complementary roles in the immune system against tumors and foreign antigens. For example, CD62L is expressed by Tcm, which predominantly migrates to nearby lymphoid tissue and reacts with tumor antigen-presenting DCs. DCs: Dendritic cells; Tcm: Central memory T cells; Teff: Effector T cells; Tem: Effector memory T cells.

Figure 4

A brief presentation of T cell exhaustion events in cancer.Both CD8+ and CD4+ T cells produce memory T cells to prevent recurrent invasion by the same antigenic component. In chronic and persistent infections, immune cells become hyperactive and exhausted. This can lead to a reduction in the T cell secretion of IL-2 and IL-12 in the primary stage. This condition can worsen when T cells begin to express PD-1. In addition, TNF-α secretion was reduced. The situation worsens when TNF-γ secretion is reduced and another immune checkpoint, CTLA-4, is expressed on the T cell surface. The T cells were exhausted and ready to die. It represents two more receptors on its surface, TIM-3 and LAG-3. This exhausted condition can be recovered through anti-PD-1 and CTLA-4 pathway drugs, vaccines, and immunotherapy. CTLA-4: cytotoxic T-lymphocyte-associated protein 4; IL: Interleukin; LAG-3: Lymphocyte-activation gene-3; PD-1: Programmed death receptor-1; TIM-3: T cell immunoglobulin domain and mucin domain 3; TNF: Tumor necrosis factor.