Key Concepts in the Segue Between the Immune System and Cancer CME
Greg M. Delgoffe, PhD; Stefani Spranger, PhD; Jason J. Luke, MD; Benjamin A. Kansy, MD; Robert L. Ferris, MD, PhD
Introduction
Research on immune surveillance, regulation, and escape has provided new avenues of therapy for cancer patients.
Immunotherapy with monoclonal antibodies (mAbs) against specific tumor targets has been more successful than active stimulation of the immune system with antitumor vaccines or cytokine therapy so far.
A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of cancers provides the basis for immune therapies and potential curative modalities for patients.
Through the tumor`s influence on its microenvironment, the immune system can be exploited to promote metastasis, angiogenesis, and growth. The following columns provide brief overviews of key components of the immune system, immune escape and immune editing, and manipulation of immunity by the tumor microenvironment allowing cancer survival and metastasis.
Certain studies in mouse models have provided various avenues of intervention, one of them being the signaling pathways of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed death 1 (PD-1), both of which are regulatory mediators for T-cell activation.
Basic immunologic observations and clinical evidence point towards promising role for using immune checkpoint-blocking antibodies for the treatment of a rapidly expanding spectrum of solid tumors. While single-agent CTLA4 or PD-1 pathway blockade has demonstrated clear antitumor activity across multiple tumor types, responding patients are still in the minority, underscoring the importance of improving present options.
Combined checkpoint blockade, to date explored with CTLA4 and PD-1 pathway-blocking agents, represents an initial bid to improve outcomes. Here, the third column provides a review of the most up-to-date clinical data from these trials, discussing both the promising clinical activity and the toxicity seen with these approaches.
The Army Within: Cells and systems in the immune response
Introduction
The mammalian immune system consists of a highly differentiated set of sensor and effector cells that can eliminate pathogens and abnormal cells with incredible precision. This is a desirable trait not only for elimination of foreign invaders but also the surveillance and destruction of premalignant and cancerous cells. This article reviews the basics of a general immune response, focusing on phagocytosis, antigen presentation, and adaptive immunity. Additionally, I will discuss the regulation of immunity and how some of these regulatory pathways are exploited in cancer.
The immune response consists of 2 interlinked systems that span dozens of cell types and many anatomic locations. The innate and adaptive systems are responsible for sensing changes in cells (intracellular pathogens, transformed cells) or by directly recognizing extracellular invaders (bacteria, fungus, helminths) and their destruction. The chemical crosstalk between these cells and systems mediates immunity as well as wound healing and the clearance of stressed or abnormal cells.
Innate Immunity -- The First Line of Defense
The first type of immune response to be recognized was probably phagocytosis: the ability to recognize and engulf something foreign, described first by Elie Metchnikoff in 1882.[1] Upon damage to a barrier, such as the skin or mucus membranes, phagocytes are recruited to the area and begin to scavenge. The first phagocytes at the site are polymorphonuclear neutrophils, which are extremely short-lived cells (approximately 5 to 90 hours) that work to contain the immediate consequences of infection.[2] They engulf pathogens and destroy them via a respiratory burst of reactive oxygen species.[2]
Macrophages are the second type of phagocyte to arrive at a site of damage, although many types of macrophages are tissue-resident cells.[3] These cells are large and granular, facilitating their killing capacity. Importantly, macrophages have a second function apart from destroying pathogens.[3] Macrophages process the pathogen into peptides and load them onto major histocompatibility complex (MHC) molecules. MHC molecules are essential in the crosstalk between innate and adaptive immunity in a process termed “antigen presentation.”[4]
T cells recognize peptides presented on the MHC molecules and become activated. Thus, macrophages are responsible for both killing foreign pathogens and directing the T-cell-mediated immune response.
While macrophages are fairly efficient at inducing cytotoxicity and as antigen presenting cells (APCs), the most efficient APC is the dendritic cell (DC).[5] DCs are relatively inefficient at clearing pathogens but are responsible for shaping the adaptive immune response .
DCs exist in (at least) 2 differentiation states, one of which is tissue resident and incredibly phagocytic.[5,6] Tissue-resident DCs sample the environment until stimulated by a “danger signal.”[7] Danger signals are emitted when pathogen-associated molecular patterns (PAMPs), present on diverse organisms but are absent in the host, bind specific receptors such as Toll-like receptors (TLRs) and others.[7]
APCs possess many TLRs that bind a number of PAMPs, such as lipopolysaccharide (LPS) found on gram-negative bacteria (TLR4), zymosan found in yeast (TLR2), or dsRNA found in viruses (TLR3).[8] With the use of TLRs, APCs can sense if what they engulf is dangerous.
Upon TLR stimulation, DCs dramatically change modes (become “mature”) and are activated. They cease their phagocytic function and instead migrate to the lymph nodes, where they upregulate the antigen presentation machinery and process the engulfed proteins.[9] They present MHC-bound pathogen-derived peptides on their cell surface and prime T cells.[10]
If the invader is new, the DC transmits information about the antigenic peptides to the T cells by interacting with the T-cell receptor (TCR) in the lymph node, and they are “primed” to recognize these peptides.
If the foreign antigens have previously invaded the host, there are T cells present that have been primed to recognize the antigens. When a DC encounters a T cell specific for that peptide, the T cell is activated and the adaptive immune system is engaged.
Search and Destroy -- The Adaptive Immune System Locks in
Evidence of adaptive immunity is found evolutionarily as far back as the jawed fish that possesses 2 key adaptations that improve on the simple “engulf and destroy” immunity of lower metazoans: the stochastic generation of receptors that can bind a vast number of epitopes and the generation of cellular memory to a previously encountered pathogen.[11]
In addition to adaptive immunity, the humoral immune response is directed by B lymphocytes.[12] B-cell development begins in the bone marrow, where a set of DNA recombination results in the random fusion of 2 to 3 protein coding cassettes among dozens that exist in the germline of the IGH/IGL loci. This results in the production of immunoglobulins (antibodies) with one of millions of specificities.[13] Antibodies that are secreted into the circulation are multivalent proteins that bind to a 3-dimensional epitope.
Antibodies have a wide array of effector functions: binding to foreign pathogens to target them for phagocytosis (“opsonization”), lysis of targets through the complement system, neutralization of infectious particles, and binding of antibody receptors on innate immune cells to confer antigen specificity.[12]
On the generation of a functional antibody molecule, naïve B cells rest until a pathogen-bound antibody clone appears.[12] When this occurs, the B cell is stimulated, facilitating its proliferation and further differentiation into an antibody-producing plasma cell.
The B cell also stimulates the DNA modification machinery to generate higher-affinity antibodies toward that pathogen.[14] At this point, B cells can form long-lived plasma cells or memory B cells that persist for life in the bone marrow, maintaining high concentrations of a specific antibody that will provide protection to specific pathogens.[15] Importantly, while B cells can initiate an immune response without the help of T cells, for antibody affinity maturation to occur, B cells require instruction from T cells.
T lymphocytes lie at the center of adaptive immunity. Cytotoxic T cells (expressing CD8) and T helper (Th) cells (expressing CD4) are derived from bone marrow-derived progenitors (thymocytes) in the thymus.[16] As they migrate through the thymic architecture, thymocytes engage in a concerted, stochastic rearrangement of their germline DNA at the TCR loci (TCRA and TCRB), akin to DNA rearrangement in B cells.[16]
This results in the generation of a vast pool of thymocyte clones, each expressing a TCR that is able to recognize a particular epitope.
At this point, thymocytes may express TCRs that could recognize self-peptides, giving rise to autoimmunity, so thymocytes undergo a process of selection. As they migrate through the thymic medulla, thymic epithelial cells present self-peptides in the context of MHC.[17]
Cells that do not respond to MHC (a nonfunctional TCR) die by neglect, whereas cells that react too strongly (autoreactive TCR) receive a strong stimulus that deletes that clone via apoptosis.[18] However, cells that can sense MHC but not react to the self-peptide receive a differentiation signal that promotes their proliferation and migration from the thymus to secondary lymphoid organs, such as spleen or lymph nodes.[18]
MHC molecules predominantly fall into 2 classes: class I and class II.[19] MHC class I is expressed by most nucleated cells and acts as a ligand for CD8-positive cytotoxic T cells.[16] The purpose of class I is, in part, to continually present a sample of peptides produced in the proteasome.[20] If a cell becomes infected or transformed, class I MHCs will subsequently become loaded with foreign or abnormal peptides.[20] Cytotoxic T cells specific for that peptide can then bind that peptide-class I complex.
MHC class II molecules are expressed predominantly by professional APCs such as macrophages or DCs.[19] Class II molecules are loaded with peptides derived from pathogens or abnormal cells that previously underwent phagocytosis.[19] In the secondary lymphoid organs, APCs present the peptide to CD4-positive T helper cells, which then go on to direct the immune response.
Cytotoxic T cells represent “boots on the ground,” recognizing infected or transformed cells through peptides presented on MHC class I.[21] On stimulation, CD8-positive T cells both lyse the target cell through the secretion of cytotoxic granules such as granzyme B and perforin and secrete IFN-?, which activates nearby macrophages.[21] CD8-positive T cells can precisely remove sources of infection, resulting in minimal collateral damage to healthy tissue.
They also are critical players in the antitumor response. As cancer cells acquire mutations, they begin to express mutated peptides, which appear foreign to the immune system (“neoantigens”) that can be recognized by cytotoxic T cells. This process, termed immune surveillance, suggests that potential cancers are often kept in check by the immune system, but the acquisition of additional mutations that promote immune escape promotes cancer progression.[22]
Th cells, expressing CD4, orchestrate the immune response. Existing in low numbers as clonal progenitors, T cells sample APCs presenting peptides on MHC class II. If a T cell reacts to the peptide-class II complex with sufficient affinity, the T cell will become activated and proliferate rapidly.[18]
During this expansion, the Th cell will also receive additional signals from the APC through cytokines.[23] These cytokines, whose expression is controlled by TLR stimulation and other environmental factors, shape the differentiation of the Th cell into effector lineages, including Th1, Th2, and Th17.[23]
These lineages are programmed by transcription factors and epigenetic modifications that prime the Th cell to secrete specific panels of cytokines when they become stimulated again.[24]
For instance, Th1 cells secrete interferon-gamma and tumor necrosis factor (TNF), which activate macrophages and direct the antiviral/antitumor responses, while Th2 cells secrete interleukin (IL)-4 and IL-13, which activate B and innate immune cells to promote antihelminth responses.[23]
Through this cytokine assistance, the immune system is directed to eliminate pathogens. Furthermore, both CD4-and CD8-positive T cells, on clearance of the pathogen, remain in the lymphatics and bone marrow as memory T cells, able to respond to that pathogen with greater vigor and persistence if ever reencountered.[25]
Figure: Anatomy of an immune response: a: Tissue-resident DCs sample the environment and encounter a virus or debris of a virally infected cell. DCs phagocytose the debris and are subsequently stimulated through TLRs via viral DNA. Debris is processed and loaded into MHC molecules as the DC begins to mature and migrate through lymphatics to the draining lymph node. B: Mature DCs now extend processes displaying viral peptides in the context of MHC. In the lymph node, the vast majority of T cells will be naïve and not virus specific, but if a virus-specific T cell meets this DC, it will receive stimulation through the TCR that promotes its differentiation and expansion. C: The activated T cells (helper and cytotoxic) now migrate via the circulation to the site of infection. CD4-positive T helper cells provide support through IFN-? and other cytokines to local innate cells and to cytotoxic CD8-positive T cells. CD8-positive T cells then scan cells in the area via their MHC class I molecules looking for its viral peptide.
If it encounters a virally infected cell expressing a viral peptide-MHCI molecule, it will secrete granzymes and perforins and deliver other cytotoxic signals to clear the infected cell. D: When the infection is resolved, these armed effector T cells return to the lymph node and circulation, primed to recognize and eliminate this particular virus if ever reencountered.
Maintaining Tolerance -- Immunoregulation
The immune system is incredibly powerful, with the specificity to remove single, infected cells and the capacity to clear away vast amounts of material. Thus, it is critical to protect self-tissues from immune attack. Central tolerance, as described earlier, is the deletion of self-reactive progenitors during thymic development. However, cells can escape negative selection, or a necessary self-antigen may appear after development.
Therefore, the immune system has several mechanisms of peripheral tolerance that act to prevent autoimmunity.
For instance, T cells have a built-in safety mechanism via which they develop “anergy.”[26]
Despite the exquisite specificity of the TCR for its antigen, TCR ligation alone is not sufficient to induce proliferation or further differentiation of naïve T cells.[26] T cells instead require a second signal, termed “costimulation,” which informs the T cell that the peptide is derived from a “dangerous” source.[27] Costimulation occurs canonically through the CD28 receptor interacting with APC-bound B7 molecules, which are upregulated via TLR stimulation of the APC.[28]
In other words, just as TLR stimulation informs the APCs that what they just ate was dangerous, the “danger” signal is also transmitted to the T cell via costimulation. T cells receiving TCR stimulation in the absence of costimulation become hyporesponsive, which is responsible for a considerable amount of peripheral tolerance.[26] B cells, too, have an analogous process.[29]
In addition, T cells have “coinhibitory” molecules, such as CTLA4 and PD-1, which, when ligated, act as negative regulators of activation.[30] While these mechanisms are important to protect against autoimmunity, they are exploited by cancer cells to promote immune escape. For instance, tumors evade the immune response in part by upregulating programmed death-ligand 1 (PD-L1), the ligand for the coinhibitory PD-1 molecule.[31] Blockade of the PD-1-PD-L1 interaction has had substantial success in the clinic for immunotherapeutic treatment of several cancers.[32-34]
In addition to cell-intrinsic forms of regulation, there are immunosuppressive cell populations that maintain peripheral tolerance. The most widely studied of these cells is the regulatory T (Treg) cell. Treg cells are a subpopulation of CD4-positive Th cells endowed with potent suppressive capabilities.[35] Treg cells are marked by the transcription factor FOXP3, which is essential for their function.[36] Loss of Treg cells via FOXP3 mutation results in a lethal autoimmune pathology called immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX).[37,38]
They function by using a variety of mechanisms (nutrient deprivation, adenosine generation, and immunosuppressive cytokine secretion) and are generated in the thymus when CD4-positive T cells react very strongly to self-antigens but not sufficiently to be deleted.[35]
However, because Treg cells are responsive to self-antigens, they can also act to hamper the antitumor response.[39] Tumors recruit Treg cells as a means of immune escape; depletion of Treg cells or inhibition of their function can result in tumor regression characterized by unrestrained antitumor responses.[40,41]
In addition to Treg cells, there are other immunosuppressive populations, including immunosuppressive macrophage populations, regulatory B cells, and tolerogenic DCs, all of which are important for immunoregulation but can be dysregulated in cancer.[42]
Conclusions
The immune system is a powerful multicellular system that plays a role in nearly every human disease. Understanding the complex crosstalk that occurs between these players is critical for appreciating the contributions of immunity to development of various pathologies. Further, the immunoregulatory pathways involved in keeping the immune response in check reveal not only how the immune system functions but also how to modulate these regulatory pathways to provide treatment strategies for autoimmune diseases and cancer.
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