Immune Regulation by Self-Recognition: Novel Possibilities for Anticancer Immunotherapy

Abstract

Circulating T cells that specifically target normal self-proteins expressed by regulatory immune cells were first described in patients with cancer, but can also be detected in healthy individuals. The adaptive immune system is distinguished for its ability to differentiate between self-antigens and foreign antigens. Thus, it was remarkable to discover T cells that apparently lacked tolerance to important self-proteins, eg, IDO, PD-L1, and FoxP3, expressed in regulatory immune cells. The ability of self-reactive T cells to react to and eliminate regulatory immune cells can influence general immune reactions. This suggests that they may be involved in immune homeostasis. It is here proposed that these T cells should be termed antiregulatory T cells (anti-Tregs). The role of anti-Tregs in immune-regulatory networks may be diverse. For example, pro-inflammatory self-reactive T cells that react to regulatory immune cells may enhance local inflammation and inhibit local immune suppression. Further exploration is warranted to investigate their potential role under different malignant conditions and the therapeutic possibilities they possess. Utilizing anti-Tregs for anticancer immunotherapy implies the direct targeting of cancer cells in addition to regulatory immune cells. Anti-Tregs provide the immune system with yet another level of immune regulation and contradict the notion that immune cells involved in the adjustment of immune responses only act as suppressor cells.

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Figures

Figure 1.

Proposed model for the involvement of anti-Tregs in immune homeostasis. A) The immune system consists of both immune effector cells (green), eg, T cells, B cells, and natural killer (NK) cells, which are responsible for eliminating elements injurious to the organism, and regulatory immune cells (red), eg, regulatory T cells, different dendritic cell subtypes, myeloid derived suppressor cells, and M2 macrophages, which control or terminate the immune response. The regulatory arm secures the unresponsiveness or tolerance to self-antigens. Regulatory immune cells suppress immunity through a number of different cellular and extracellular factors (red arrow), including the stimulation of inhibitory T cell pathways (eg, PD-1 and CTLA-4); the release of immune suppressive cytokines, like TGF-β and IL-10; and the expression of metabolic enzymes, like IDO and Arginase. These immune-tolerance mechanisms may also be exploited by cancer cells to achieve immune escape, which becomes more pronounced with disease progression. Hence, many of the mechanisms considered helpful in autoimmune settings are used by tumors to suppress immune responses towards malignant cells in cancerous settings. A detailed understanding of the factors involved in immune evasion in malignant conditions is essential for the development of novel, immune-therapeutic treatment modalities in cancer. B) Regulatory immune cells (red) express normal self-proteins (large yellow), which are subsequently processed into peptides (small yellow) and presented on the cell surface by HLA molecules, where they are recognized by anti-Tregs (blue-gray). Hence, anti-Tregs can promote local immune suppression by the secretion of effector cytokines or by directly eliminating regulatory immune cells (red arrow). Similarly, they can eliminate malignant cells that express their cognate targets. Open questions remain of how and when these anti-Tregs are induced or become activated and whether they play a role in the pathogenesis and development of autoimmune diseases. C) Self-reactive anti-Tregs (blue-gray) may avoid thymic selection and peripheral tolerance and are able to react to and even eliminate regulatory immune cells (red), thereby influencing general immune reactions. It must be assumed that anti-Tregs themselves are hampered by the suppressive effects of their targets. Hence, under normal physiological conditions equilibrium between immune activation and suppression may indeed be necessary to maintain immune homeostasis. The role of self-reactive effector and suppressor cells in immune-regulatory networks may thus be miscellaneous. GrB = granzyme B; HLA = human leucocyte antigen; IDO = indoleamine 2,3-dioxygenase; IFN-γ = interferon gamma; PD-L1 = programmed death-ligand 1; TCR = αβ T cell receptor; TNF-α = tumor necrosis factor alpha.

Figure 2.

Activation of anti-Tregs boosts immunity in vitro. Anti-Tregs are able to boost specific immunity against virus or tumor antigens in human peripheral blood mononuclear cells (PBMC). When stimulating PBMC with a known HLA-restricted, viral T cell epitope and interleukin-2 (IL-2), virus-specific T cells (green) begin to expand. The activation of anti-Tregs by the costimulation with an anti-Treg epitope (bottom), eg, programmed death-ligand 1 (PD-L1) or indoleamine 2,3-dioxygenase (IDO) peptides, facilitates further expansion of virus-specific T cells and a decrease in the numbers of Tregs (red), compared with cultures costimulated with an irrelevant control peptide, eg, an HIV peptide epitope (top). This “supportive” effect of anti-Tregs on immune effector cells may well be mediated in several direct and indirect manners, which may depend on the anti-Treg antigen. Of note, IDO+ cells may well be immune suppressive by other means than by the expression of IDO. Hence, the IDO+ cells may in addition express, eg, Arginase, PD-L1, and immune regulatory cytokines (eg, interleukin-10 and transforming growth factor (TGF)–β). IDO-specific anti-Tregs may therefore not only reduce IDO-mediated suppression directly but in addition further immune suppression mediated by IDO+ regulatory cells.

Figure 3.

Exploiting anti-Tregs for anticancer immunotherapy. Cells in the tumor microenvironment (light gray) express multiple proteins, eg, inhibitory cytokines, ligands, and cognate receptors that downmodulate the antitumor activity of immune effector cells including cytotoxic T lymphocytes. Some of these inhibitory proteins are expressed by tumor cells (purple) themselves, whereas others are expressed by tumor-infiltrating suppressive cells including Tregs (red), dendritic cells (DC) (dark red), myeloid cell types (Mφ) like MDSC, and M2 or tumor-associated macrophages (light red). Multiple immune inhibitory and costimulatory pathways in the tumor microenvironment may thus be targeted by therapeutic manipulation of anti-Tregs (green-blue), eg, by therapeutic vaccination. Anti-Tregs recognizing HLA-restricted epitopes (yellow) from antigens like PD-L1, IDO, and FoxP3 are able to eliminate (red arrows) regulatory immune cells as well as cancer cells. Hence, the activation of anti-Tregs by vaccination may directly target immune inhibitory pathways in the tumor microenvironment, modulate immune regulation, and potentially alter tolerance to tumor antigens. Because immune-suppressive cells might antagonize the desired effects of therapeutic cancer vaccines, the addition of anti-Treg antigens would consequently be easily implementable and highly synergistic. FoxP3 = forkhead box P3; HLA = human leucocyte antigen; IDO = indoleamine 2,3-dioxygenase; PD-L1 = programmed death-ligand 1; TCR = αβ T cell receptor.