Tumor Immunology

3 Tumor Immunology

Volker Schirrmacher

Introduction

Tumor immunology deals with the interaction between the immune system and cancer. Its origins can be traced back to Paul Ehrlich at the beginning of the twentieth century. The field developed rather slowly at the beginning, but this changed with the advent of newer technologies. In order to establish tumor cell lineages, methods for culturing cells needed to be established. When transplanting tumors out of mice or rats, they had to descend from inbred lineages to avoid genetic differences that may have had an effect on experimental outcomes. Quantitative studies of antitumor immune reactions in vitro depended on new techniques for tissue culture as well as on the presence of certain growth factors and cytokines.

Further advances were made when monoclonal antibodies became available, which permitted discrimination of cells within the immune system. With the help of flow cytometry and cell sorting these cells could then ultimately be separated.

After the first inbred mouse lineages became available in the 1940s and 1950s, findings for tumor-specific immune reactions against chemically induced transplantation tumors were obtained (14). First, experimental immune therapy studies demonstrated effects against metastases in rat tumor models by vaccination in the autonomous host (23). The existence of so-called tumor-associated transplantation antigens (TATA) on chemically induced tumors was shown, but it took sometime before their nature as well as the nature of TATA-detecting receptors on T lymphocytes also became known.

The development of monoclonal antibodies using hybridoma technology at first resulted in heightened expectations. It was hoped that the tumor-specific antibodies (or “magic bullets”) postulated by Paul Ehrlich could now be discovered. Ever since the 1980s, much effort has been channeled into the identification of tumor-specific antigens using monoclonal antibodies. While some of the antibodies thereby obtained improved the understanding and insight into tumor diagnosis, disappointment was great when it was realized that these isolated tumor-reactive monoclonal antibodies were not really tumor specific. Despite the help of monoclonal antibodies, the nature of TATAs found on chemically induced tumors was not discovered fully.

Identifiable Tumor Antigens

Since it became known that the tumor-transplant rejection process was an immune reaction caused by T cells, T-cell immunology became the focus of subsequent studies. It took many decades of research to fully understand the nature of the antigen-specific T-cell receptor (TCR) as well as that of antigens that are recognized by TCRs found, for example, on virus-infected cells or tumor cells. This field of specific anti-tumor T-cell immunology only began when autologous tumor antigens, induced by a combination of cell immunology and genetic methods, were identified.

It was then noticed that TCRs recognize bits of intracellular proteins made up of linear peptides of nine to 15 amino acids on the surface of target cells. The recognition requires the binding of peptide and of so-called major histocompatibility complex (MHC) molecules to the TCR. With the aid of such proteins intracellular peptides are transported to the surface of the cell, where they are then recognized by TCRs.

In the 1990s the first tumor antigens on human tumors were identified (5, 20). These, too, are peptides presented by human MHC molecules (HLA) on the surface of tumor cells for recognition by receptors on tumor-specific cytotoxic T lymphocytes (CTL). Recently an antibody-based method was added that enables identification of new human tumor antigens through serological recombinant expression cloning (SEREX). Using specific CTL as well as the SEREX method, multiple human tumor antigens were discovered on various types of tumors and have been characterized in the last few years.

Studies using animal models showed that the immune system has the ability to ward off tumor cells and that T lymphocytes play a major role in this rejection reaction. With the help of adoptive transfer studies and analysis of those tumor variants that escaped a rejection reaction, the vital role of CTL in vivo was demonstrated. In these immune-escape variants the CTL epitope was lost.

In cancer patients tumor-specific CTL can be activated through in-vitro stimulation of their lymphocytes. The study of melanoma variants, resistant to some but not all of such CTL clones, showed that melanomas were able to express different tumor antigens that can be distinguished by CD8+ T cells. Many such antigens have been characterized and identified at the molecular level (5, 20). The mechanism of expression has also been studied to determine tumor specificity.

There are five main categories of tumor antigens as defined by CD8⁺ CTL:

1. common tumor-associated antigens

2. differentiation antigens

3. antigens caused through mutation

4. overexpressed antigens

5. viral antigens.

The efficiency of a tumor rejection reaction probably depends on the individuality of TATA expression on the tumor cells as well as the absence of mechanisms of tolerance (8). Since CD8⁺ CTL have been shown to directly lyse tumor cells or destroy even large parts of a tumor in vivo, much effort was directed to the study of immune therapy of cancer using CD8⁺ CTL. Clinical vaccination trials with tumor antigens defined by CD8⁺ CTL have given clues as to therapeutic effects, even though the impact of immune response was weak and only temporary.

There are two reasons why interest has shifted to include also tumor antigens recognized through MHC class II-restricted CD4⁺ T cells: primarily, CD4⁺ T cells are capable of identifying tumor antigens (11) that are distinct from the antigens defined by CD8⁺ T cells, and additionally, there are known synergistic effects between CD4⁺ and CD8⁺ immune cells in tumor regression.

Identification of antigens that stimulate CD4⁺ T helper cells and attempts to integrate these into an antitumor immune reaction could help to improve immune-therapeutic approaches in the future.

Effector Cells and Mechanisms of Antitumor Immunity

T effector cells play a central role in almost all adaptive immune responses. Activation of mature naïve T cells that have never had antigen contact through professional antigen-presenting cells is the decisive initial step in immune response. A complex series of stimulatory effects results in T-cell activation. Costimulatory molecules play an important role in this process, in which the balance between negative and positive signals determines immune response and tolerance. Antigen-specific triggering, via a TCR complex or antibodies against CD3 molecules associated with the TCR, delivers signal 1 of activation (Fig. 3.1).

When CD28 molecules are triggered on T cells at the same time, this leads to signal 2 and naïve T cells can be activated. Cytotoxic T cells, (CTL) can effectively be activated by means of combined stimulation with anti-CD3 and anti-CD28 molecules and can expand in culture with the use of cytokines and growth factors. Following direct costimulation of CD8⁺ T cells through melanoma cells transfected with CD28 ligand (B7), tumor rejection was observed in the animal model (24).

Besides the already mentioned T lymphocytes there are a number of other cells of the immune system that contribute to natural immunity and also display cytotoxic activity against tumor cells. They include the natural killer cells (NK cells) (Fig. 3.1), activated macrophages/monocytes, and granulocytes, as well as dendritic cells (DCs). It is generally true that such cells need to be triggered by molecules before they exert cytotoxic effects.

Trigger molecules of cells in the natural immune system include, for example, receptors for the constant region of immunoglobulins, so-called Fc receptors (1) (Table 3.1), as well as the recently discovered toll-like receptors (TLRs) (13).

Not all of the Fc receptors belong to the activating Fc receptors. Some transmit inhibitory signals.

These receptors are activated physiologically via the constant regions of antibody molecules, which themselves bind to specific cellular targets, thereby generating immune complexes. Normally these are IgG antibodies that serve as a binding link between natural and specifically acquired (adaptive) immunity in antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In the ADCC mechanism, effector cells of the natural system (for example NK cells or monocytes or macrophages) are bound through antibody bridges to their specific tumor targets and thereby activated to become cytotoxic.

Antibodies can be found in the serum of patients with cancer; they help identify new tumor antigens using SEREX (21)

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