Cancer immunity and clinical oncology
- The vertebrate immune system
- Cancer immunosurveillance
- Tumour antigens
- Cancer immunotherapy in clinical practice
- Immune intervention against virus-associated cancers
- Strategies to improve immunotherapy in cancer
- Concluding remarks
Patients develop immune-mediated defence mechanisms against cancers, which are referred to as the ‘three E’s’:
- elimination—corresponding to immunological control of the tumour or immunosurveillance;
- equilibrium—the process by which the immune response iteratively selects/promotes less immunogenic tumour variants; and
- escape—when the immunologically sculptured tumour expands in an uncontrolled manner.
Human cancer antigens
These represent proteins that are uniquely (over)expressed in malignant tissues and function as target for immunotherapy. They can be divided in following categories:
- cancer–testis (CT) antigens—silent in healthy tissues, except germ cells, but expressed in various cancer types (e.g. NY-ESO-1, which is probably the most immunogenic CT antigen known);
- differentiation antigens of certain cell types, such as melanocytes or breast cell epithelia;
- unique tumour-specific antigens that are the products of genetic alterations;
- virus-encoded antigens in virus-associated cancers; (5) ubiquitous antigens that are overexpressed in tumours.
Antigen-specific immunotherapy in cancer patients focuses either on (1) T-cell-mediated approaches or on (2) antibodies. T cells are generally directed against endogenous tumour-derived proteins that are processed and presented in the context of major histocompatibility complex molecules, whereas antibodies are directed at molecular targets expressed at the cancer cell surface.
Monoclonal antibodies—these are now established and integrated in many treatment regimens in cancer medicine, e.g. rituximab (targeting CD20) in non-Hodgkin’s lymphoma and trastuzumab (targeting Erb2/HER2) in breast cancer).
Cancer vaccination—the keys to efficient vaccination are;
- availability of an immunogenic, tumour-associated antigen;
- a route, schedule, and packaging of the antigen that will induce an optimal immune response in vivo;
- the combination of antigen with an adjuvant to support the induction of a strong immune response in vivo;
- sustained immunity; and
- inhibition of regulatory pathways, such as CTLA-4, PD-1, and Tregs.
At this early stage of development, cancer immunotherapy should be offered only in the context of carefully monitored clinical trials conducted by experienced clinical research teams.
The importance of the immune system in the control and defence of cancer is no longer in question. The origins of the field of cancer immunotherapy can be traced back to William Coley who, in the 1890s, observed that potentially fatal bacterial infections could induce an effective antitumour response in patients with partially resected tumours. Enthusiasm for this approach has waxed and waned over the last several decades. It is now well known that the immune system has the ability to recognize tumour-associated antigens (TAA) displayed on human malignancies and to direct cytotoxic responses to these targets. While the discovery of treatment modalities such as radiotherapy and chemotherapy focused the interest of the scientific community for decades, recent improved understanding of the molecular basis of immune recognition has revived the interest in cancer immunotherapy. In this chapter, we discuss the principles of tumour immunity, the tumour antigens that can be recognized by the immune system, cancer immunotherapy strategies, and selected clinical trials of immunotherapy.
The vertebrate immune system
The vertebrate immune system has evolved to combat pathogens that continuously threaten the integrity of the host. A wide variety of innate or natural resistance mechanisms have coevolved with adaptive immunity in vertebrates. The major function of these complex and efficient defence systems is to protect the host against deleterious infections with pathogens, such as bacteria, fungi, viruses, or parasites. This requires that the immune system discriminates between pathogens and self-antigens while precisely recognizing a vast array of antigens.
Within hours after an infection, the innate resistance system is activated. This evolutionary ancient defence system functions by pattern recognition, which is not target specific. It rapidly discriminates self and nonself, which leads to immediate inhibition of replication and spread of pathogens and gives the adaptive immune response time to develop. The innate response is composed of soluble and cellular effector mechanisms, such as the complement system, interferons, acute phase reactants, granulocytes, macrophages, and natural killer (NK) cells.
The adaptive immune response can be divided into either humoral (antibody) responses or cell-mediated (T-cell) responses. Antibodies recognize and bind to conformational determinants on soluble or cell surface proteins, and can kill the cell by either antibody-dependent cellular cytotoxicity (ADCC) or complement-mediated cell lysis. Antibodies alone, or in combination with chemotherapy, can be highly effective in mediating tumour regression in haematological malignancies, and have progressively also been introduced into clinical practice for the treatment of solid tumours.
Conversely, T cells recognize antigenic peptides presented on the cell surface in the context of major histocompatibility (MHC) antigens with their T cell receptor (TCR). The TCR consists of an α and a β chain with constant and (hyper)variable regions, the latter interacting with the antigen MHC complex. Each T cell has only one type of antigen receptor, and is of single specificity. Theoretically, the T-cell repertoire can consist of more than 1010 different antigen receptors.
However, the actual repertoire is considerably smaller, because most recombinations are not productive or because some will result in receptors that recognize self-antigens and are usually deleted. Interaction of thymocytes through their TCR with self-MHC molecules in the thymic medulla is a survival signal for these thymocytes: they will be positively selected and are MHC-restricted as a result.
Most autoreactive T cells are deleted in the thymus by a process called negative selection, which takes place in the medulla and is thought to be mediated by macrophages and dendritic cells (DC) presenting self-antigens to immature thymocytes. However, some antigens may be absent from the thymus, especially those that are expressed only in peripheral tissues or those that are only present during certain periods of life (e.g. proteins involved in lactation).
There is now evidence that many tissue-specific proteins are expressed ectopically in the thymus, and that AIRE, a thymus-specific transcription factor, may regulate this ectopic expression. However, as it is unlikely that all peripheral proteins are present in the thymus in sufficient quantities to mediate negative selection, there is an apparent need for induction and maintenance of peripheral T-cell tolerance in order to avoid autoimmunity (see below).
The activation of mature T cells is a complex process that requires a minimum of two signals. The first signal is mediated by the interaction of the TCR, expressed on T lymphocytes, with a specific antigenic peptide that has been processed by and presented on the surface of a professional antigen-presenting cell (APC) bound to an MHC molecule. Intracellular signalling, resulting in cellular proliferation, is then conveyed through an intracellular portion of the CD3 complex, which is associated with the TCR. The second costimulatory signal is also delivered by APCs through members of the B7 family of surface molecules that bind to their targets expressed on T cells. APCs also secrete critical cytokines such as interleukins IL-12 and IL-15 that contribute to T cell activation and memory. In the absence of costimulation, T cells may enter a state of nonresponsiveness or anergy.
Lafferty and coworkers first demonstrated the requirement for specialized stimulator cells for T-cell activation in a series of classical experiments, in which they observed that the rejection of histoincompatible organ grafts is dependent on donor leucocytes trapped in the graft. Based on their ability to express MHC class II and costimulatory molecules and to take up antigens, B cells, macrophages and dendritic cells are thought to have the capacity to stimulate naive T cells. During the past 10 years, however, a large body of evidence has accumulated suggesting that dendritic cells are the only cells fulfilling all criteria of an APC.
In the 1990s, Charles Janeway proposed that the induction of adaptive immunity depends on a distinct, innate recognition event involving primitive receptors, termed pathogen recognition receptors (PRRs). These receptors bind conserved microbial structures, the so-called pathogen-associated molecular patterns (PAMPs). Macrophages, dendritic cells, mast cells, neutrophils, eosinophils, and NK cells express different PRRs. A major class of PRRs consists of the Toll-like receptors (TLRs). In mammals at least 10 members of the TLR family have been described to date. TLRs specifically recognize microbial components, such as lipopolysaccharide (LPS), unmethylated CpG motifs, bacterial peptidoglycans, double-stranded (ds) RNA that naturally occurs during the replication of some viruses, flagellin, and many more.
In addition to direct recognition of pathogens by receptors on the dendritic cell or inside the dendritic cell, indirect means of dendritic cell activation by pathogens have been described: dendritic cell maturation is induced in response to inflammatory mediators such as tumour necrosis factor α (TNFα), IL-1β, or prostaglandin E2 (PGE2) that are secreted in response to infections or by ligation of surface CD40 by activated CD4+ T cells (T-cell help).
The molecular understanding of PRRs has led to a better appreciation of adjuvants in cancer immunotherapy. A classic example is William B Coley’s observation from the New York Hospital that some patients with sarcomas had spontaneous tumour regressions following a superficial streptococcal skin infection. Seeking to harness the power of the immune system, Coley deliberately infected some of his inoperable patients with erysipelas to stimulate tumour regression. He later refined this approach by using heat-killed Streptococcus pyogenes in combination with heat-killed Serratia marcescens—a mixture that is now commonly known as ‘Coley’s toxin’. Administration of Coley’s toxin to patients with soft-tissue sarcomas resulted in response rates over 50%.
Today, it is recognized that the induction of an efficient and protective immune response depends on the interaction between naive antigen-specific T cells and mature dendritic cells. Upon maturation dendritic cells have reduced capacity for antigen uptake, but change their pattern of homing receptors (e.g. up-regulation of CCR7), which allows them to migrate into the T cell areas of secondary lymphoid organs, and up-regulate costimulatory molecules. These changes are crucial for efficient priming of naive antigen-specific T cells.
Cancer immunity and clinical oncology - Concluding remarks
Significant advances have been made in the field of cancer immunotherapy over the last decade. The most important step forward has been the identification of tumour antigens with immunogenic potential. The utilization and improvement of cancer immunotherapy in the clinic demands carefully conducted and coordinated but discovery-oriented translational research in the form of clinical trials that include thorough monitoring of immune and clinical responses.
As selective outgrowth of antigen-loss variants due to immunoediting may occur during vaccination of cancer patients, antigen expression patterns of the tumour and metastases should be monitored during immunotherapy, if possible, followed by surgical resection of antigen-negative tumours.
At this rather early stage of development cancer immunotherapy should be offered to cancer patients only within carefully monitored clinical trials of experienced clinical research teams. In addition, it may be rewarding to include patients with early-stage disease in immunotherapy trials, because immunoediting of the tumour and subversion of the immune response by the tumour is presumably less pronounced in those patients.
The keys to efficient cancer vaccination are:
- availability of an antigen known to be a strong immunogen in cancer patients;
- the route, schedule, and packaging of antigen to induce an optimal immune response in vivo;
- combination of antigen with an adjuvant, to support the induction of a strong immune response in vivo;
- long-term immunizations, and
- inhibition of regulatory signals, such as CTLA-4, Tregs, and PD-1.