Targeted Anti-Tumor Immunotherapy Using Tumor Infiltrating Cells

Abstract

In the tumor microenvironment, T cells, B cells, and many other cells play important and distinct roles in anti-tumor immunotherapy. Although the immune checkpoint blockade and adoptive cell transfer can elicit durable clinical responses, only a few patients benefit from these therapies. Increased understanding of tumor-infiltrating immune cells can provide novel therapies and drugs that induce a highly specific anti-tumor immune response to certain groups of patients. Herein, the recent research progress on tumor-infiltrating B cells and T cells, including CD8⁺ T cells, CD4⁺ T cells, and exhausted T cells and their role in anti-tumor immunity, is summarized. Moreover, several anti-tumor therapy approaches are discussed based on different immune cells and their prospects for future applications in cancer treatment.

Keywords: B cells; CD4+ T cells; CD8+ T cells; T-cell exhaustion; anti-tumor immunity; anti-tumor therapy; tumor immunotherapy; tumor microenvironment.

Figure 1

History of cancer immunotherapy. Major breakthroughs on the receptors, strategies, and drugs used for Immunotherapies are indicated.

Figure 2

Clinical trials of drugs targeting of the anti‐tumor immune targets. The most progress of clinical transformation of targets mentioned in table 1 are indicated. Some drugs targeting those targets have reached phase 1(BTLA and TLR8), phase 2 (LAG‐3, VISTA, Siglec‐15, 4‐1BB, GITR, and B7‐H3) or phase 3 (Tim‐3, TIGIT, and SphK1) of clinical trials. Some drugs have already received FDA approval (PD‐1, PD‐L1, and CTLA‐4).

Figure 3

Anti‐tumor targets associated with CD8⁺ T cells. These targets include co‐inhibitors on the surface of immune cells or intracellular proteins affecting the activity of CD8⁺ T cells. The blockade of these targets can lead to more effective therapeutic effects.

Figure 4

Tumor‐infiltrating CD4⁺ T cells in the TME. The roles of CD4⁺ T cells, especially Treg cells, in the TME have received increasing research attention. Several receptors and intracellular proteins that affect the differentiation and the immunosuppressive function of T_reg cells have been identified, many of which can become potential targets. Treg cells not only directly inhibit the activity of CD8⁺ T cells, but also exert immunosuppressive functions via tumor‐associated macrophages (TAMs) and other CD4⁺ T cells.

Figure 5

Stages and mechanism of T cell exhaustion. A| The four stages of T cell exhaustion are controlled by a series of proteins, the mechanism of which is complex and involves several environmental factors and trigger molecules. B| Roles of TOX in CD8⁺ T cell exhaustion. TOX, one of the most important proteins during T cell exhaustion, regulates the expression of a series of genes and determines the direction of cell differentiation.

Figure 6

B cells in the TME. A| Functions of B cells in anti‐tumor immunity. B cells various functions in the TME, including cytokine release, antibody production, antigen presentation, and ADCC. Thus, B cells have promising potential as targets for anti‐tumor therapy strategies. B| Role of B cells in chemotherapy. On the one hand, B cells inhibit the differentiation of CD8⁺ T cells by secreting exosomes and hydrolyze the ATP released by tumor cells into adenosine. On the other hand, B cells increase the ratio of Teff/Treg through the complement system, ultimately enhancing anti‐tumor immunity.

Figure 7

Overview of cancer therapies and other tumor‐related immune cells. In addition to traditional cancer treatment methods, such as surgical resection, radiotherapy, and chemotherapy, new therapies, such as hyperthermia, PDT and immunotherapy, have emerged. Immunotherapy, the most popular alternative treatment to treat tumors, has many strategies. T cells, as well as many other cell types, have become targets of immunotherapy strategies.