19 - Cancer and the Immune system

Question 1

Tumor growth and metastasis (overview figure)

Answer 1

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.

Question 2

carcinomas

Answer 2

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.

Question 3

sarcomas

Answer 3

derived from mesodermal connective tissues, like bone, fat and cartilage

Question 4

carcinogens

Answer 4

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)

Question 5

Genes associated with cancer controll cell proliferation and survival (categories

Answer 5

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)

Question 6

Oncogenes

Answer 6

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)

Question 7

tumor-suppressor genes

Answer 7

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.

Question 8

apoptotis genes

Answer 8

these genes can either be inhibitors or promoters of the apoptotic pathway.

example: bcl-2 (anti-apoptosis gene).

Question 9

Malignant transformation

Answer 9

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

Question 10

hallmarks of cancer

Answer 10

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

Question 11

Tumor antigens (categories)

Answer 11

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.

Question 12

tumor-specific Ags (TSA)

Answer 12

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.

Question 13

tumor associated Ags (TAA)

Answer 13

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.

Question 14

deleted

Answer 14

deleted

Question 15

Mechanisms for preventing cancer

Answer 15

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.

Question 16

three main ways the immune system is throught to control or inhibit cancer

Answer 16

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.

Question 17

immunoediting

Answer 17

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.

Question 18

innate inhibitors of cancer

Answer 18

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.

Question 19

Adaptive cellular processes and the cells involved in cancer eradication

Answer 19

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.

Question 20

The role of cytokines in cancer immunity

Answer 20

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)

Question 21

chronic inflammation and cancer

Answer 21

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)

Question 22

Tumor-enhancing Abs

Answer 22

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.

Question 23

Immunosuppression in the tumro envorinment

Answer 23

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.

Question 24

Tumor cells evolve to evade immune recognition and apoptosis

Answer 24

• 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.

Question 25

Types of immunotherapy availible to treat cancer

Answer 25

1) mAbs that target specific surface molecules (either naked or with toxins conjugated)
2) adoptively transferred DCs that have been loaded with TAAs and expanded in vitro, followed by reinfusion into the patient.
3) adoptively transferred T cells that have been collected from the patient and expanded or modified in vitro, and then reintroduced
4) CAR T cells generated by adding a chimeric receptor recognizing a tumor Ag to autologous T cells that are expanded and later re-infused
5) checkpoint blockade, incolcing the use of mAbs specific for one or more of the surface molecules

Question 26

Chemical or drug therapies for cancer fall into 4 broad categories

Answer 26

in increasing order of specificity for tumor cells:

• Chemoteraphies, aimed at blocking DNA synthesis and cell division
• hormonal therapies, which can interfere with hormone receptor-positive tumor cell growth
• targeted therapies, such as small-molecule inhibitors of tumors sensitive to these drugs
• immunotherapies, which induce or enhance specific antitumor immune responses. This is the only one that aims to activate an immune response against the cancer cells.

Question 27

mAbs in cancer treatment

Answer 27

mAbs can be produced for spesific idiotypes (the Ag-binding region) of tumor cells (at least in B-cell cancer). Th mAbs bound to the cancerous cells, and helped complement and ADCC mediated lysis, leading to regression. However, this is expensive and time-consuming. Less specific mAbs can target lineage-distinctive antigens on cell surfaces. In the B cell example, rituximab targets CD20. This means that non-cancerous B cells will die, but these can be regenerated from HSCs.

Abs can also be coupled with toxic substances (“guided missiles”, called antibody-drug conjugates (ADCs)). Can be delivered at high local concentrations to cancer cells, sparing nonmalignant cells. If the conjugate is a toxin, it is called immunotoxin.

Many tumors express significantly increased levels of GFs/GF receptos, which are promising targets for mAbs.

Question 28

Tumor-specific T cells in cancer treatment

Answer 28

TILs don’t always have a super good effect against tumors, and has somewhat been replaced by adoptive cell transfers, as the T cells are supressed by Tregs. adoptive cell transfers = peripheral cells. Cells are more long lived than Abs, so that is one big advantage.

CAR = chimeric Ag-Receptor T cells.
Begin with autologous T cells isolated from the patient.
in vitro, add the gene for a chimereic tumor Ag-specific receptor.
infusion back into patient.

Question 29

Theraputic vaccines in cancer treatment

Answer 29

immunogen = the protein/Ag used in vaccines (theraputic or prophylatic (normal)).

overall disappointing, low effect.

theraputic cancer vaccines are designed to redirect or enhance the anticancer response, and use strategies like infusion of autologous DCs with tumor Ags, in vitro stimulation and expansion of autologous cells, or presentation of hidden tumor neoantigens to the immune system.

Question 30

Manipulation of comodulatory signals, using checkpoint blockade

Answer 30

mAbs targeted towards CTLA-4(cytotoxic T-lymphocyte-associated protein 4) & PD-1 (programmed cell death protein) have been shown to help against tumors.

Side effects: generalized dysregulation of the immune response.