Immunology Chapter 19: Cancer and Immune System
what occurs in the three phases of immunoediting?
1.Elimination: This is the traditional view of the role of the immune system in cancer, roughly analogous to immunosurveillance—identification and destruction of newly formed cancer cells. 2.Equilibrium: a state of balance between moderate destruction of neoplastic cells with survival of a small number of cancer cells. Ample clinical evidence now suggests that the equilibrium phase can continue for decades after the emergence of a tumor, whether it is treated or not. In fact, equilibrium states of cancer may be much more common than previously appreciated. 3.Escape: This is the final phase of immunoediting, when the most aggressive and least immunogenic of the residual tumor cells begin to thrive and spread, often thanks to help from immune pathways. you have a healthy tissue but maybe there is a transformation because of an issue in the DNA replication but then it is repaired so the tissue is healthy again. But now, when the tissue is infected with a virus such as the epstien barr virus , the immune system recognizes it and starts killing cells infected with the virus. So the first phase is elimination: you have cytotoxic t cells, NK cells, etc. and these are able to recognize cells that are infected by virus for instance and are able to destroy them. - this part is called cancer immunosureillance and it is the elimination step of immunoeditiing. BUT the bottom line is that the immune system is able to recognize cells that are altered - nonself - and destroy them so that we go back to healthy tissues. Now in this particular case we have destruction of cancer cells. now the second phase which can last a very long time is equilibrium and this is a phase where the cancer does not persist and it is kept in check - it does not expand but it is never eliminated. And in this particular case, the equilibrium phase involves the following - some cells that are infected by the virus or express TAAs are recognized by the immune system by CD8+ t cells or NK cells and they are eliminated via apoptosis. But in some cases the apoptotic gene is defecent in the cancer cell. well this cell is not going to get edit - it is going to presist. or maybe the cancer cell becomes mutated that it is no longer recognized by the NK cells. in theses particular cases you begin to get cells that are not able to be touched by the immune system. So some cells are going to be destoyed but some are not able to be touched. At some point the number of untouchable cells is going to presist and tip the balance towards the third phase which is escape. in the third phase escape - the cancer progresses. the players recruited are a little different. we still have our cytotoxic t cells, and NK cells. but we also get Tregs (which suppress the immune response), M2 macrophages which are involved with tissue repair. these give a tolerance environment where the immune system is accommodating the cancer cells.
Anticancer drug therapies generally fall into four loosely organized categories: what are they?
Anticancer drug therapies generally fall into four loosely organized categories: •Chemotherapies aimed at blocking DNA synthesis and cell division •Hormonal therapies, which interfere with tumor-cell growth •Targeted therapies such as small molecule inhibitors of cancer (ex. cytokine inhibitors) •Immunotherapies, which are any treatment designed specifically to revive, initiate, or supplement in vivo antitumor immune responses. These therapies focus on activating an immune response against the cancer cells, creating signals or cells that will guide the immune system in the right direction, allowing the body to take care of the rest. This can take the form of humanized monoclonal antibodies that will bind selectively to cancer cells, peptides from tumor antigens administered in a way that induces CTL activity, or molecules that release cancer-generated blocks to natural immune activation. - are here to help the natural immune response against the cancer cell or to help the body recognize and identify which cells are cancerous so the body can destroy them - there are a number of strateriges to do this but they all involve using the bodies natural responses to rid the host of cancer cells.
Both innate and adaptive immune responses participate in the detection and eradication of cancer. Specifically:
Both innate and adaptive immune responses participate in the detection and eradication of cancer. Specifically: Several nonadaptive cells and processes are involved in cancer recognition and removal, including NK cells and M1-type macrophages, and possibly eosinophils, along with the cytokines produced by these cells, such as IFN-γ, TNF-α, and IL-5, respectively. Antitumor CTLs are the adaptive cell type most associated with cancer eradication, although activated DCs and TH1-type cells likely also assist in this pathway. Anti-tumor antibodies can bind to the surface of cancer cells, allowing cells with Fc receptors, such as NK cells and macrophages, to induce ADCC in tumor targets. The cytokines most connected with antitumor responses include both type I and type II IFNs, TNF-α, and IL-12; all are associated with strong TH1-cell and CTL responses. Good prognosis indicators: CTLs to TREGs ratio, high frequency of tumor-specific CD8+ T cells. the cells involved in elimination/equlibirum phase are CTC, NK cells, and hormones and cytokines that are involve in the recruitment of immune cells to the site of infection the cells involve in the escape are cells like TGF-β, IL-10, etc. cells that dampan the immune response and promotion of tolerance.
What advantages do neoplastic cells display?
By definition, all neoplastic cells display a selective growth advantage over their peers. Malignant cells display alterations in key cellular processes and microenvironmental conditions: cell fate decisions, genome maintenance, cell survival, genetic instability, metabolic changes, and immune response patterns. A subset of cells within a tumor may be the real engines of tumor growth. This subset, called cancer stem cells, displays true unlimited regenerative potential and is the major producer of new cells to feed the tumor. Nonstem cells each undergo unique mutations and differentiate in novel ways. This gives cancer an advantage in terms of renewal potential and immune evasion. Nonstem cells constitute the bulk of the growing edges of the tumor and thus serve as the primary immune targets -like decoys. These rapidly mutating cells express an ever-evolving set of new protein markers, with the potential to serve as targets for the immune response. However, there is little risk if these proteins are recognized and lead to immune destruction; their undifferentiated stem cell parent remains as a source of replacement. so if you think of those neoplastic cells or cancer cells - why do they grow so well? well they have a growth advantage. if one has removed the breaks (such as the tumor suppressor genes) then you get increased growth. Some of these advantages might be increased proliferative signaling, or maybe they do not die as well, they can invade other cells, or maybe they have enabled replicative immorally which allows them to divid and replicate really quickly. Whats interesting is one advantage is they might be able to induce angiogenesis - which will become more important in a couple of slides but what you have to remember is that cancer cells also need nutrient in order to grow - and that typically these nutrients are brought to those cancer cells by blood vessels (such as O2) therefore without the growth of blood vessels there would not be any sustained cancer growth. Therefore their ability to induce angioengsis which is the growth of blood vessels is a particular characteristic of cancer cells. whats also interesting is that when looking at cancer growth you do not just have one type of cancer cells but multiple different types of cancer cells. And in fact whats interesting is that you have group of cells called the cancer stem cells (CSC) these cells are really similar to stem cells except they are linked to cancer - for instance they have the potential to divid and differentiate, really providing the tumor cells so that the tumor can grow. The cells on the outside of these tumors can be targets of the immune system and of immunotherapy, etc.
how are different types of cancer classified?
Cancers are classified according to their embryonic tissue origin: Carcinomas are tumors that develop from epithelial origins •Skin, gut, or epithelial linings Sarcomas derive from mesodermal connective tissue (these represent a minority of cancers, ~1%) •Bone, fat, and cartilage tissue Lymphomas, myelomas, and leukemias derive from hematopoietic stem cells (~9% of cases) •Leukemias are early stage development of bone marrow cells •Lymphomas and myelomas (B cells) arise from cells after migration out of bone marrow cancers can be classified by the different types of tissue they infect.
What produces a tumor? what is a neoplasm? what does it mean if a tumor is benign? what does the term metastasis refer to? what is a malignant tumor?
Cells that give rise to progeny with the ability to expand in an uncontrolled manner will produce a tumor or neoplasm. A tumor that is not capable of indefinite growth and does not invade the healthy surrounding tissue is said to be benign. A tumor that continues to grow and becomes progressively more invasive is called malignant. The term cancer refers specifically to a malignant tumor. In addition to uncontrolled growth, most malignant tumors eventually exhibit metastasis or spread, whereby small clusters of cancerous cells dislodge from the original tumor, invade the blood or lymphatic vessels, and are carried to distant sites where they take up residence and continue to proliferate. So what is cancer? in its most fundamental form it is a disease that results from unregulated growth of a group of cells. A cell that starts to grown in an unregulated fashion is called a tumor or neoplasm. more often than not these tumors are benign and they do not invade surrounding tissues and they stay in one general area. However in some cases these benign tumors can progress to become more aggressive and they start to expand into surrounding tissues known as a malignant tumor which is cancerous. Malignant tumors can start to metastasis and can gain access to the blood stream or lymph vesicles to travel to different areas of the body and start to appear in different places.
what is the tumor reactive T cell statergy?
Early observations of lymphocyte infiltration into solid tumors suggested that these cells might be a possible source of tumor-specific immunity. Subsequent research has shown that in many cases, tumor-reactive T cells (called TILs, or tumor-infiltrating lymphocytes) can be isolated from the peripheral blood, lymph nodes, and solid tumors of patients with cancer. These tumor-specific T cells can be expanded and reintroduced into patients. The therapeutic strategy is as follows: 1.Cells obtained from tumors, tumor-draining nodes, or peripheral blood 2.Once obtained, the cells are expanded ex vivo using IL-2 cytokine to overcome anergic states 3.Patients are depleted of lymphocytes to create a niche for the new cells 4.The expanded cells are reinfused another option in addition to antibody Immunotherapies is the use of T cells. In many cases patients had tumor reactive T cells but it was never enough to rid the host of the cancer. so the stratergie here is to use lymphocytes that were infiltrating tumors and expand them using IL-2 to overcome anergic states. the patients are then depleted of t cells and then reinfused with the T cells specific for the tumor so that they could target the tumor
What is a monoclonal antibody?
Monoclonal antibodies (mAbs) can be used to direct the immune response to tumor cells. When this approach was first conceptualized, the idea was that mAbs recognizing tumor-specific surface markers would selectively attach to these malignant cells, mark them for destruction by leukocytes, and deliver a payload of antibody-conjugated toxins. One early success came from the treatment of a 64-year-old man with terminal B-cell lymphoma that had metastasized to the liver, spleen, and bone marrow. Because this was a B-cell cancer, the membrane-bound immunoglobulin on all the cancerous cells had the exact same idiotype (antigenic specificity). Researchers produced mouse mAb specific for the idiotype (the antigen-binding region) of this B-lymphoma. When this anti-idiotype antibody was injected into the patient, it bound specifically only to the cancerous B-lymphoma cells that expressed that particular immunoglobulin. Since these cells are susceptible to complement- or ADCC-mediated lysis, the mAb activated the destruction of these cells without harming other cells. After four injections with this anti-idiotype mAb, the tumors began to shrink and the patient entered an unusually long period of remission. monoclonial antibodies are antibodies of the same isotype. They are an antibody that recognizes one specific epitope and they can be used to tag very specific tumor cells. and by tagging them with antibodies now the bodies immune system can respond. so we are guiding the immune system towards one particular group of cells which happens to be the tumor cells. we are looking for antibodies that bind the Fab region because they are going to bing to cells that express our receptor. so when injected into the patient those antibodies will bind to those B cells that are over proliferating and tagging them allowing them to be targeted by NK cells. A more general therapy for B-cell lymphoma based on the fact that most B cells, whether cancerous or not, express many copies of lineage-distinctive antigens on their surface. For example, therapeutic mAbs that target the B-cell marker CD20, such as rituximab, are widely used to treat non-Hodgkin's lymphoma. While rituximab treatment does lead to the destruction of noncancerous B cells, we know the immune system is capable of regenerating new B cells from hematopoietic stem cells, somewhat blunting this side effect. CD20 is a cell marker that is expressed on B cells and rituximab binds specifically to cells expressing CD20 therefore it will bind to B cells and and target them for distraction - the consenques is that all B cells will be eliminated but with that are the cancerous B cells which is a hit we are willing to take Another example: in 25% to 30% of women with metastatic breast cancer, a genetic alteration of the tumor cells results in the increased expression of human epidermal growth factor-like receptor 2 (HER2), which is encoded by the neu gene. HER2 is expressed in only trace amounts in normal adults. Because of this difference in HER2 protein levels, a humanized mAb against HER2, called Herceptin, has been successfully used to treat breast cancers that overexpress neu.
From an immunologic perspective, cancer cells can be viewed as altered self cells that have escaped normal growth-regulating mechanisms. This makes recognition and response by the immune system challenging; while we want to be rid of these cells, we also do not want to mistakenly stimulate an autoimmune attack on healthy tissues. The good news is that surveillance for cancer cells is one of the regular maintenance roles of the immune system. The bad news is that cancers, as a rule, find ways to avoid this immune recognition. In this chapter we will review some background information on cancer and introduce the most common types of the disease. This is followed by extensive discussions of how the immune response deals with cells that become cancerous, and how these cells avoid engagement with the immune system. Finally, we touch on the vast range of therapies available to treat cancer, focusing on a host of new immunotherapies.
1.Terminology and the formation of cancer 2.Tumor antigens 3.The immune response to cancer 4.Anticancer immunotherapies
What occurs during cellular transformation?
Cellular transformation occurs as the result of multiple gene mutations that accumulate in several genes over time, and gradually subvert the normal checks on cell growth and survival. Induction of malignant transformation appears to evolve in distinct phases, referred to as initiation, promotion, progression, and metastasis. •Initiation: change or mutation alters cell proliferation that, by itself, does not lead to malignant transformation •Promotion: accumulation of preneoplastic cells •Progression: further genetic alterations allow for rampant cell proliferation and acquisition of new mutations to potential cancer-promoting genes •Metastasis: final stage where solid tumors lose adhesion and move outside original site there are several phases that lead to the appearance of cancer. initiation --> promotion --> progression --> and metastasis 1. initiation - the initial or unlucky event that starts a cell down a path of transformation to become a tumor eventually. 2. promotion: accumulation of cells that are in the pre-tumor stage 3. progression: an accumulation of defects that are leading to uncontrolled growth 4. metastasis: when the cancer starts to spread in the picture, we are looking at the GI track. one of the cells as a mutation that leads to the loss of its APC gene which is a tumor suppressor gene.
what are carcinogens? what occurs in burkitt's lymphoma?
Cancer-causing agents (carcinogens) and random events that damage DNA (e.g. ionizing radiation), including some viral infections and chromosomal translocations, can accumulate into a condition that allows unregulated cell proliferation and cellular transformation. Most cases of Burkitt's lymphoma arise following a chromosomal translocation that moves part of chromosome 8, containing the c-myc gene, to the Ig heavy-chain locus on chromosome 14, shown in more detail in (b). (c) In some cases, the entire c-myc gene is inserted near the Ig heavy-chain enhancer. (d) In other cases, only the coding exons (2 and 3) of c-myc are inserted at the μ switch site. Myc functions as a transcription factor controlling the behavior of many genes involved in cell growth and proliferation. We are going to look at burkitt's lymphoma to understand how certain agents (carcinogens) can cause cancer - so sometimes the events that are linked to the appearance of a tumor can be due to the exposure to one particular carcinogen. Carcinogens can be chemicals, but also can be viruses as in the case for burkitt's lymphoma - the carcinogen is the epstein-barr virus. In this particular case, after infection by the epstein-barr virus, there is an exchange of DNA sequences between chromosome 8 and chromosome 14 that results in the transfer of sequences that encode the gene c-myc onto chromosome 14. C-myc is a transcriptional factor that controls the expression of genes involved in cell proliferation - so something you clearly would not want over expressed. when the c-myc gene is tranfered onto chromosome 14 it is switched onto the part of the chromosome that encodes for hemoglobin's heavy chain. As a result we have over-expression of c-myc and over proliferation of those cells.
what are therapeutic vaccine?
Most vaccines are designed to initiate an immune response before the onset of infection or disease; these are called prophylactic vaccines, or just vaccines. Therapeutic vaccines, on the other hand, aim to enhance or redirect an existing immune response after infection or exposure to the relevant antigen. Therapeutic cancer vaccines are designed to redirect or enhance the anticancer response and use strategies like infusion of autologous DCs with tumor antigens, in vitro stimulation and expansion of autologous cells, or presentation of hidden tumor neoantigens to the immune system. In the example shown here, autologous DCs are isolated from a patient's blood and cultured with a fusion protein consisting of the prostate cancer-specific antigen PAP and the APC-activating cytokine GM-CSF (PAP/GM-CSF). DCs take up and process these antigens, after which they are infused into the patient in order to stimulate a T-cell response against PAP expressed on tumor cells in the prostate. a third statergy has to do with therapeutic vaccines. - most vaccines are prophylacitic that is are trying to prevent a disease. well these vaccines are therapeutic which means we are trying to design a way for T cells in the patient to recognize cancer cells. dendritic cells from the patient are isolated from the patients blood and they are cultured with a prostate antigen fusion protein. which this means is that the prostate antigen is going to be taken up by the dendritic cell and processed via the exogenous pathway and be displayed on its surface via MHC class I and II. this dendritic cell is then going to be infused into the patient and therefore these cells will be presenting peptides from the tumor to T cells and at a particular point the T cells will become activated and use those peptides to find the target with is the tumor.
what are tumor antigens? what are the two different classes?
Neoplastic cells are still self cells. As such, all or most of the antigens associated with these cells are subject to the same tolerance-inducing processes that maintain homeostasis and inhibit the development of autoimmunity elsewhere in the body. However, in some instances, cancer cells may produce unique or inappropriately expressed antigens that can be detected by the immune system. Collectively, these are called tumor antigens. Most tumor antigens give rise to peptides that are recognized by the immune system via presentation by self MHC class I molecules. In fact, many of these antigens have been identified by their ability to induce the proliferation of antigen-specific CD8+ lymphocytes. Tumor antigens recognized by human T cells fall into one of four groups based on their source: •Antigens encoded by genes exclusively expressed by tumors •Antigens encoded by variant forms of normal genes that are altered by mutation •Antigens normally expressed only at certain stages of development •Antigens that are overexpressed in particular tumors we are now moving on to tumor antigens. even though cancer cells are still self cells, they can still sometimes express cell surface proteins that are a little different - such as proteins that are markers for tumors which are known as tumor antigens. The reason they are called tumor antigens is bc one could isolate CD8+ t cells can are specific for those tumor antigens - so clearly that means that there is an immune response against those tumor antigens. so one might wonder - so where do they come from? there are two different classes: 1. tumor specific antigens (TSAs) and 2. tumor associated antigens (TAAs). The TSAs might be those tumor antigens that appear only on the cancer cells - so basically only the tumors are going to express these antigens.
what are oncogenes? what are tumor suppressor genes? what are apoptosis genes?
Normal tissues maintain homeostasis through a tightly controlled process of cell proliferation balanced by regulated cell death, or apoptosis. An imbalance at either end of the scale can encourage development of a tumor. The genes involved in these homeostatic processes work by producing proteins that either encourage or discourage cellular proliferation and survival. Oncogenes are typically DNA sequences that encode proteins involved in promoting cell growth and proliferation, such as transcription factors, growth factors (and their receptors), or intracellular signaling molecules. Tumor suppressor genes act naturally as anti-oncogenes or inhibitors of cell growth and proliferation, becoming agents of transformation when they fail to function, such as during DNA repair or in blocking progression through cell cycle checkpoints. Apoptosis genes: when the DNA sequences involved in apoptosis, or programmed cell death, are not functioning properly they also can aid in cellular transformation, encouraging the survival and proliferation of neoplastic cells. typically we think of three different types of genes that can lead to the appearance of cancer. These events either lead to the uncontrolled growth of the cell - so something that promotes growth. OR the barrier that controls growth is removed. 1. oncogenes: genes that encode proteins (such as myc for instance) that can promote the growth of cells - so cell proliferation. Growth factors are good examples, any of the cytokine and cytokine receptors that we have seen that are involved in HSC survival are all oncogenes. 2. conversely, tumor suppressor genes are genes that typically are a barrier to uncontrolled growth. And you could image that the removal of these genes or inactivation of their gene products by mutation for instance, might lead to uncontrolled growth as well. so similar to oncogenes these molecules can be of different functions - they can be DNA repair proteins, etc. 3. apoptosis genes: not all cells have the same life span - some are programed to die very early as in effector t cells which have a couple days life span - but memory cells that have a fairly long life span. and defect in the apoptosis genes will favor the appearance of cancers.
what is checkpoint blackade?
One of the most promising new anticancer immunotherapies is checkpoint blockade, where monoclonal antibodies recognizing co-inhibitory molecules (e.g., CTLA-4, PD-1, or PD-L1) are used alone or in combination to interrupt negative regulation of tumor-specific T cells. Early support for the hypothesis that manipulation of co-stimulatory signals could prove beneficial in cancer immunotherapies was presented in 1992, when Peter Linsley and colleagues demonstrated complete tumor regression in 40% of tumor-bearing mice injected with melanoma cells that had been transfected with CD80/86. The next year, Sarah Townsend and James Allison used a similar approach to prophylactically vaccinate mice against malignant melanoma. Normal mice were first immunized with irradiated, CD80-transfected melanoma cells, and then later challenged with malignant melanoma cells lacking this costimulatory molecule. This "vaccine" was found to protect almost 90% of the mice when they were challenged with the wild-type, malignant cancer cells. the statergie here is to remove to breaks on the costimlatory signal which can be inhibitor.
what are checkpoint blockage therapies?
The most recent cancer immunotherapy involves using mAbs to block surface molecules involved in dampening the immune response of T cells. Specifically, antibodies against CTLA-4 or PD-1, both inhibitory receptors on T cells, as well as antibodies against the PD-L1 ligand (frequently expressed on cancer cells) can block these checkpoint molecules. These antibodies work in lymphoid tissues (to enhance immune stimulatory signals) and at the site of the tumor (blocking inhibitory pathways), allowing activated CD8+ T cells free rein to migrate to tumor sites and carry out their destructive programming, with less interference from regulatory cells and other immunosuppressive cues. These strategies are called checkpoint blockade therapies.
what are chimeric antigen-receptor (CAR) t cells?
The newest addition to adoptive T-cell therapy for cancer is CARs. Chimeric antigen-receptor (CAR) T cells begin with autologous T cells isolated from a patient with cancer. In vitro, scientists add the gene for a chimeric tumor antigen-specific receptor, followed by infusion of these cells back into the patient. this is a new evolution of the tumor reactive t cell stragery. It uses the targeting properties of an antibody (bc remember a t cell has to bind to a peptide presented by a MHC molecule where as an antibody just binds to an antigen) so in CAR t cells the statergy is to get T cells from the patient and then make those T cell receptors specific for those tumor antigens but instead of using antibodies and ADCC to kill the target cells we are using t cells which are now equipt to kill those cancer cells on their own.
What is immunoediting?
These observations led to the idea that the immune system exerts a dynamic influence on cancer, inhibiting some tumor cells but also sculpting or editing them in a Darwinian process of selection: those that survive immune winnowing are better able to outwit the immune response and thus have a survival advantage. Thus was born the term immunoediting, to describe how the immune system engages in both positive (antitumor) and negative (protumor) actions that help to sculpt the tumor, determining which cells will be eliminated and which will remain. So, in the end, the antitumor immune responses select for toughest cells. Three phases are proposed: 1.Elimination: attacking the cells that can be targeted 2.Equilibrium: state of balance between destruction/survival of "best" cells 3.Escape: most aggressive/least immunogenic cells thrive and spread the previous 3 experience led individuals to believe that the immune system is able to influence cancer - its able to recognize cancer cells and in come cases destroy them, and then in some cases they some of them go. Thus was born immunoediting. the hypothesis is that the immune system can both find and destroy cancer cells but at the same time some cancer cells are going to be able to grow and evade the immune system. In some cases immunoedititing will lead to the appearance of cancers cells that are enabled to be recognized and destroyed my the immune system. there are three phases in immunoeditiing. 1. elimination 2. equilibrium 3. escape
what are tumor-associated antigens?
Tumor-associated antigens, or TAAs, are not unique to neoplastic cells. Instead, these represent normal cellular proteins and thus are prone to the usual self-tolerance mechanisms. Most TAAs are proteins expressed only during specific developmental stages, such as in the fetus, or at extremely low levels, but which become induced or up-regulated in tumor cells (e.g. neu in breast cancer). Those derived from reactivation of certain fetal or embryonic genes, called oncofetal tumor antigens, normally only appear early in embryonic development, before the immune system acquires immunocompetence. When transformation of cells causes these fetal proteins to appear at later stages of development on the neoplastic cells of the adult, they can be recognized as aberrant and induce an immunologic response. in some cases of TAAs, these antigens may not normally be expressed on the surface of cells in adults but they are highly expressed during emboygenesis or during development in the embryo. Is this common - well in fact, cancer cells actually quite frequency re-express proteins that are embryonic. (they need to grow quickly just as a baby needs to grow fast during a short period of time) TAAs might be self proteins that are over expressed on the surface of the cell or they are non expressed in normal amounts that corresponds to the age of the person a good example is the gene neu which encodes for a HER2 which is a growth factor receptor. neu is almost absent in adult cells but in individuals with breast cancer it is expressed in high amounts whether TAAs or TSAs they are going to look foreign and attack the attention fo the immune response
what are tumor-specific antigens?
Tumor-specific antigens are unique proteins that may result from DNA mutations in tumor cells that generate altered proteins and, therefore, new nonself antigens or epitopes. Cytosolic processing of these proteins then gives rise to novel peptides that are presented with MHC class I molecules, which can lead to induction of a cell-mediated response by tumor-specific CD8+ T cells. In this way, TSAs contain some "foreign" or new peptides, and thus become natural targets for immune recognition. Importantly, TSAs can be found in some virally induced tumors, where sequences from the infecting virus are recognized by the immune system. these are the proteins that are expressed from DNA that is expressed in tumor cells and they express altered proteins. Altered proteins might be a proteins that is a completely new protein - for instance an in the HPV infection. Cells that are virally infected with express proteins that are not self. OR they can be proteins that have been modified through mutations so much so that they will be recognized as nonself or foreign. In these particular cases, a normal cell might express an altered self peptide following infection by a virus which can be recognized by the immune system.
Unfortunately, the selective pressure applied by the antitumor immune response can select for escape mutants, or cells that evade the immune response. How do these cells evade surveillance and editing?
Unfortunately, the selective pressure applied by the antitumor immune response can select for escape mutants, or cells that evade the immune response. How do these cells evade surveillance and editing? Transformed cells employ several strategies to evade the immune response: •reduced MHC class I expression •anti-apoptotic responses (e.g. defects in CD95 or NKG2D expression) •poor or blocked costimulation of T-cell responses, immunosuppressive microenvironments. The lack of proper second signal may lead to clonal anergy in T cells and immune tolerance to cancer cells. issue: lets say you have a cancer cell that is expressing high amounts of MHC class I molecules, it is picked up my a CD8+ CTC and destroyed. But if this cancer cell expressed less MHC molecules it can become invisible to the immune system and then some mutants are going to presist and invade the immune response. Now you might wonder - since its expressing low MHC class I molecules it will be picked up by NK cells and killed via apoptosis. BUT some of these cells might have a mutation in their apoptotic genes allowing them to survive and expand. so remember that cancer is a progression of events.
is there evidence that indicates that the immune system can response to cancer?
YES. Data collected in the past few decades from both animal models and clinical studies have clearly defined a role for the immune response in tumor cell identification and eradication. In addition to destroying virus that lead to cellular transformation or regulating inflammation, the immune system actively identifies and eliminates transformed cells. The term immunosurveillance was coined to convey the idea that the immune system continually monitors for and destroys neoplastic cells. There are numerous lines of evidence, but let's focus on three: 1.Immune-suppressed individuals, such as patients with AIDS or transplant recipients receiving immunosuppressive drugs, have a much higher incidence of several types of cancer than do individuals with fully competent immune systems. 2.In the mid 1990's, work in model animals suggested that natural immunity could eliminate tumors. For example, RAG2 knockout mice, which lack the enzyme necessary to undergo V(D)J recombination and thus fail to generate T, B, or NKT cells, were found to be more likely to spontaneously develop cancer as they age and were more susceptible to chemical carcinogens. 3.When tumors from wild-type and rag2-/- mice are transferred into syngeneic wild-type recipients, the tumors coming from wild-type animals grew aggressively in their new hosts as expected. However, up to 40% of the tumors taken from immunodeficient rag2-/- mice were rejected by healthy syngeneic recipients. This suggested that tumors growing in immune-deficient environments are more immunogenic, that is, they are easier for the immune system to recognize than those arising in an immunocompetent environment. there are many pieces of evidence that point to the fact that the immune system might be able to attack cancer cells. we are going to focus on 3. 2. without RAG2 those mice did not have an adaptive immune system bc they could not make B or T cells were more susceptible to cancer as they aged
