19 - Cancer and the Immune system Flashcards
Tumor growth and metastasis (overview figure)
1) A single cell develops altered growth properties at a tissue site, which may be corrected via DNA repair
2) The altered cell proliferates, forming a mass of localized tumor cells, or a benign tumor
3) The tumor cells become progessively more invasive, spreading to the underlying basal lamina. The tumor is now classified as malignant
4) the malignant tumor metastasizes by generating small clusters of cancer cells that dislodge from the tumor and are carried by the blood or lymph to other sites in the body.
metastasis = spread.
carcinomas
tumors that develop from epithelial origins such as skin, gut, or the epithelial lining of internal organs and glands.
includes skin cancers, majority of cancers of the colon, breast, prostate and lung.
sarcomas
derived from mesodermal connective tissues, like bone, fat and cartilage
carcinogens
agents that cause cancer
formaldehyde, benzene, some pesticides, physichal agents like asbestos, and ionizing radioation (can cause DNA mutations).
Infection of certain viruses (most integrate into host genome and disrupt chromosomal DNA)
Genes associated with cancer controll cell proliferation and survival (categories
disruption of genes that either encourage or discourage cellular proliferation and survival can cause cancer.
three major categories:
- oncogenes (sequences that encourage growth and proliferation)
- tumor-suppressor genes (sequences that discourage or inhibit cell proliferation
- apopotosis genes (sequences that control programmed cell death)
Oncogenes
proto-oncogene = normal cellular gene involved in some aspect of cell growth nd proliferation. If mutated/dysregulated, it can become an oncogene.
example: c-neu (in some breast cancers the increased trc of this gene is linked with cancer development and disease progression)
tumor-suppressor genes
aka anti-oncogenes, encode proteins that inhibit cell proliferation. normally prevent cells from progressing through the cell cycle inappropriately, functioning like brakes on a car.
TP53 gene. mutation in this = responsible for 60& of cancers. encodes p53, a nuclear phosphoprotein with multiple cellular roles, incl growth arrest, DNA repair, and apoptosis.
apoptotis genes
these genes can either be inhibitors or promoters of the apoptotic pathway.
example: bcl-2 (anti-apoptosis gene).
Malignant transformation
promotion of cancerous stage happens from a series of small changes. this multistep process of clonal evolution is driven by a series of somatic mutations. Early genetic chances that begin the cascade = driver mutations. Later followed by passenger mutations.
induction of malignant transformation appears to evolve in four phases: initiation, promotion, progression, metastasis.
Initiation: involves changes or mutations in the genome that alter cell proliferation potential but do not, in themselves, lead to malignant transformation.
Promotion: occurs when preneoplastic cells begin to accumulate. Generally small tumors and the cells are still amenable to repair mechanisms.
These two stages can last long, and can be susceptible to immune-mediated detection and chemopreventive agents (disease can be reversible)
prograssion: more quickly than the previous stages, genetic alterations allow rampant cell proliferation. tumor size grows.
metastasis: when one or more of the cells in the tumor
hallmarks of cancer
DNA-alterations that cause cancer are generally clustered against these ffunctions:
- cell fate determination
- genome maintanence
- cell survival
other conditions include genome instability, altered metabolic pathways, chronic inflammation, and immune avoidance patterns.
cancer stem cells = the cells in the tuors that really drive the growth. they can produce many cells, some with mutations that leads to an ever-evolving set of new protein markers, with the potential to serve at targets for the immune response
Tumor antigens (categories)
tumor antigens = unique or inappropriatly expressed antigens that are expessed by cancer cells and detected by the immune system.
4 categories:
- Ags encoded by genes exclusively expressed by tumors
- Ags encoded by variant forms of normal genes that are altered by mutation
- Ags normally expressed only at certains stages of development
- Ags that are overexpressed in particular tumors.
the first 2 = tumor specific Ags
The latter 2 = tumor associated Ags.
tumor-specific Ags (TSA)
unique proteins that may result from DNA mutations in tumor cells that generate altered proteins ans, therefore, new nonself Ags or epitopes. cytosolic processing of these give novel peptides to be presented on MHC, which can induce an immune response.
tumor associated Ags (TAA)
not unique to tumor cells, but normally only expressed in certain developmental stges (like fetuses) or at extremely low levels. In tumors they are upregulated.
This derived from fetal or embryonal genes are called oncofetal tumor antigens.
TAAs also include products of some oncogenes. example: epidermal growth factor (EGF) receptor levels are 100x greater in some tumors than in normal cells.
deleted
deleted
Mechanisms for preventing cancer
intrinsic: nucleotide excision repair (NER), which encourages cell senescence (permanent cell cycle arrest) and DNA repair, or even apoptosis, at the first signs on unregulated growth
extrinsic mechanisms involve environmental signals that instruct a cell to activate internal pathways leading to growth arrest and/or apoptosis in order to prevent noeplastic cell spread.
dispurption of epithelial cell associations with the exreacellular matrix sue to malignant transformation triggers death signals that block prolferation and spread of these contact-dependent cells.
three main ways the immune system is throught to control or inhibit cancer
1) destroying viruses that are known to transform cells
2) rapidly eliminate pathogens and regulating inflammation
3) actively identifying and eliminating transformed cells, aka immunosurveilance
chronic inflammation and immune-mediated selection for malignant cells may actually contribute to cencer spread and survival.
immunoediting
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
Cancer immunoediting can be divided into three sequential phases:
- elimination
- equilibrium
- escape
Elimination = traditional view of the role of the IS in cancer, roughly analogous to immunosurveillance - identification and destruction of newly formed cancer cells.
Equilibrium = balance between moderate destruction of neoplastic cells and survival of a small number of cancer cells. can continue for decades after the emergance of a tumor (treated or untreated).
Escape = final phase of immunoediting, the most aggressive and least immunogenic of the residual tumor cells begin to thrive and spread, often due to help from immune pathways.
innate inhibitors of cancer
NK!!!
NK cell recognition mechanisms use a series of surface receptors that respond to a combination of activating an inhibiting signals delivered by self-cells (chap 12).
- can detect “missing self”, i.e., downregulated MHC I.
- DAMPs released by tumor cells. (“altered” or “induced-self” signal, through the receptor NKG2D).
various forms of cellular stress, incl viral infection, heat shock, UV radiation, and other agents that induce DNA damage, can trigger the expression of the ligands for these activating NK-receptors.
When activating signals are induced by DNA damage pathways, NK cells may be able to distinguish cancerous and precancerous cels from healthy neighbour cells. Once engaged, they use cytilytic granules (incl compounds like perforin) to kill the target cell.
Nks also secrete IFN-y, a potent anticancer cytokine that encourages MHC expression in DCs, which in turn stimulates strong CTL responses.
Activated macrophages are also important!! They cluster around tumors, and the presence of proinflammatory macrophages (like M1 type) is correlated with tumor regression.
Both NK and macrophages express Fc receptors, enabling them to rec bound Abs and mediate ADCC. TNF-α also has anti-tumor activity.
Adaptive cellular processes and the cells involved in cancer eradication
tumor cells have increased expression of PD-L1, which inhibits engagement of CTLs by binding to their PD-1s.
TILs = tumor infiltrating lymphocytes = combination of T cells, NKT cells, and NK cells.
Frequency of TILs at the site of the tumor correlates with a survival prognosis (high = high, low=low).
High freq of tumor-specific CD8+, or elevated CTL/Treg tario, is generally associated with enhanced survival.
B cells can generate anti-tumor Abs that can foster tumor rec and -lysis. using their Fc receptors, NK cells and macrophages participate in this response, mediating ADCC. However, some antitumor Abs (called enhancing Abs) can actually block CTL access to the tumor-specific Abs, helping the tumor cells survive.
The role of cytokines in cancer immunity
Cytokines associated with TH1 pathway and CTL responses are most associated qith cancer eradication. IFN-y and the regulatory components of this pathway are clearly important in cancer elimination. IFN-y can exert direct antitumor effectos on transformed cells, incl increasing MHC I, making the cells better targets for CD8+ rec and -destruction. IFN types I and II (alpha, beta, gamma) can foster tumor cell removal.
IL12 is also important against cancer. It drived T cell pathways; encorages DCs to activate a strong TH1 and CTL response, which helps to create an antitumro environment.
TNF-α is also anticancerous. It induces hemorrhage and necrosis for the tumor. It can also have tumor promoting effects.
(TGF-β, IDO, IL-10 and chronic inflammation are part og protumor microenvironments)
chronic inflammation and cancer
chronic or ongoing inflammation can create a protumor microenvironment via several mechanisns;
1) systeins inflammatory responses induce cellular stress (i.e., ROS), increasing mutation rates in cells
2) the GFs and cytokines secreted by leukocytes often induce cellular proliferation, and during mutation events, nonimmune tumor cells can acuire the ability to respond to these growth stimulators.
3) inflammation is proangiogenic and prolymphangiogenic, increasing the growth of local blood vessels. supplies tumors with oxygens, and allows cells to migrate (metastasis)
Tumor-enhancing Abs
CML = cell mediated lympholysis (in vitro lysis of target cells by CTLs). anti-tumor Abs can in some cases act as a serum blocking factor.
Presumably the Ab binds to TSA and masks the Ags from CTLs. In many cases the blocking factors are not Abs alone, but rather Abs complexed with free tumor Ags. these complexes may also inhibit ADCC by binding to Fc receptors on NK/macrophages, and blocking their activity.
Immunosuppression in the tumro envorinment
The presence of immunosuppressive cells (MDSCs (myeloid-derived suppressor cells), M2 macrophages, Tregs) and the cytokines they produce (IL-10 and TGF-β) in the tumor microenvironment can foster tumor survival and immune evasion.
IDO also important (inhibits TH1 responses, as does TGF-β).
TGF-β can possible bluck local DC activation and inhibit T cell function.
Tumor cells evolve to evade immune recognition and apoptosis
- Reduced MHC expression. NK should rec these cells, but they also generally down-regulate the expression of ligands tha tbind to the activating receptor for NK, and thus avoid the NK cells.
- Resistance to apoptotic signals. Due to chnages in the extrinsic response system, namely cell-surface death receptors, as well as intrinsic mechanisms based on mitochondrial pathwayd for apoptosis. Fas cell death receptor (CD95) and TRAILR, as well as NKG2D (NK cells), are examples of receptors that recieve external signals for apoptosis. Decreases in proapoptotic signalling components (like Bcl-2 superfamily), or increases in anti-apoptotic compinds (survivin, inhibitor of apoptosis) .
Poor costimulatory signals and immunorepressive microenvironments.
tumors have failry poor immunogenicity, lack costimulatory molecules, meaning they can’t give the second signal needed for T cell activation. Unless there is an overwhelming number of APCs present, the T cells will only recieve 1 signal.
