Lecture 3: Cancer and the Immune System

Question 1

What is tumor immunology?

Answer 1

The study of the immune response to tumors

This focuses on tumor antigen, tumors interaction with the immune system, and how we can use/boost the immune system to fight cancer

Question 2

Normal cells growth and development

Answer 2

Typically a highly regulated process

New cells are rapidly produced, but only when needed: to grow during development, during regular tissue turnover, or during wound healing and tissue repair

Cell division is inhibited when sufficient cells are present
Cells have intentionally limited life spans that involve programmed cell death called apoptosis

Question 3

What are protooncogenes?

Answer 3

Regulatory genes that promote cell division

Question 4

What are tumor suppressor genes?

Answer 4

Genes that produce inhibitory signals that suppress growth and cellular division

When these signals are absent tumors can arise through unchecked rapid growth and cell division

Question 5

Drawbacks of tumors’ similarity to normal cells

Answer 5

Because tumors arise through improperly regulated systems used for normal growth, they can look quite similar to normal tissue and aren’t automatically eradicated by the immune system

Question 6

What are the two tumor varieties?

Answer 6

Benign and malignant

Question 7

Benign tumors

Answer 7

Possess a capsule that surrounds the abnormal growth

These masses lack the ability to invade other tissues

Question 8

Malignant tumors

Answer 8

Do not possess a capsule

Are able to invade other tissues and disrupt bodily functions to the point of causing death

Question 9

Metastasis

Answer 9

When malignant cells travel throughout the body via the blood and lymph systems, generate new foci or colonies of tumor cells, and disrupt body functions so severely that the patient dies

Question 10

Conversion of normal cells to malignant cells is a:

Answer 10

Process

That occurs slowly over time and includes 3 phases

Question 11

What are the 3 stages of conversion to cancer?

Answer 11

Induction Phase
In situ Phase
Invasion phase

Question 12

Induction Phase

Answer 12

Can take months to years to occur

Are due to environmental insults such as: chemical carcinogens, oncogenic viruses, and radiation

Often multiple mutations need to occur, and some cells are genetically predisposed to developing these mutations

Question 13

In situ Phase

Answer 13

Neoplastic cells (uncontrolled cellular proliferation) have arisen and are confined to the tissue of origin

If these neoplasms are malignant they will proceed to the invasion phase

Question 14

Invasion Phase

Answer 14

Malignant cancer spreads from the tissue of origin

First to nearby lymph nodes, and later through the lymph system and blood to other sites in the body

Question 15

Dysplastic cells

Answer 15

Abnormal cells that are the precursors to neoplasms

Question 16

Monoclonal origin, heterogeneous proliferation, and immune evasion of cancer

Answer 16

Initially cancer tends to arise from one cell.

However, because of rapid growth and dysregulation tumors are prone to errors and mutations so they become heterogeneous over time

This ability to mutate helps cancer cells evade detection by the immune system

Question 17

Detection issues as a result of cancer mutations

Answer 17

Not only does cancer escape the immune system as it mutates

It also can evade specific chemotherapeutic agents and specific tumor markers as their surface marker expression changes as a result of mutations

Question 18

Anaplastic

Answer 18

Tumors that appear similar to fetal or embryonic tissue (developing tissue)

These tumors are classified as poorly differentiated because their makers differ from fully developed and differentiated cells of adult tissue

These growths tend to be more aggressive, resulting in a worse prognosis for the patient

Question 19

TNM System

Answer 19

This is the tumor classification system

T size of the primary tumor
N involvement of adjacent lymph nodes
M detection of metastasis

Question 20

Immunosurveillance

Answer 20

The immune system is constantly roving the body, looking for cancer/infections/etc.

The immune system is also constantly waging war against cancer/potential cancer to kill it or at least keep it in check

However, this never ending war acts as an evolutionary/Darwinian type pressure on cancer cells similarly to how animals evolve according to Darwinian principles of natural selection/survival of the fittest

Question 21

Immunoediting

Answer 21

The actual response to immune pressure on cancer cells that results in selection of the most resilient tumor cells

Question 22

Three phases of immunoediting

Answer 22

Elimination
Equilibrium
Escape

Question 23

Elimination

Answer 23

The immune system eradicates easily detected tumor cells, but a few remain due to advantages obtained through mutations. This is a form of selection.

Question 24

Equilibrium

Answer 24

The tumor is under control, however resistant cells are beginning to proliferate. Selection pressure continues, so more of the tumor volume is resistant to the immune system as resistant cells proliferate and begin to enter the escape phase and non-resistant cells continue to die off. The immune system is selecting for mutations that help cells evade detection.

Question 25

Escape

Answer 25

The tumor grows and expands completely unchecked as a majority of the cells are immune resistant.

Question 26

HSP and immuno-detection

Answer 26

Typically tumor cells produce HSP (Heat shock protein) which allow them to be detected by dendritic cells which then pass the message on via the WNT signaling system to T and NK cells to destroy tumors

However, some tumor cells produce less HSP and evade detection. There is no way to make cancer cells produce more HSP

Question 27

MHC and immuno-detection

Answer 27

Typically tumor cells present abnormal protains on their MHC1 class receptors to mark themselves for apoptosis

However, some tumor cells may not present their MHC1s (for typical cells) or MHC2s (if you have mutated immune cells for specific types of cancer)

Question 28

Tumor growth rate as evasion

Answer 28

Some tumors simply proliferate too quickly to be kept in check by the immune system, even if some cells are being regularly destroyed.

Question 29

PD1/PDL1 pathway evasion

Answer 29

Some tumor cells express PD1, which binds to the PDL1 receptor on T cells (normal checkpoint to prevent overzealous immune response), deactivating them so that the tumor isn’t triggered to go through apoptosis like it should

Question 30

2 Types of Tumor antigens

Answer 30

Tumor Specific Antigens

Tumor Associated Antigens

Question 31

Tumor Specific Antigens

Answer 31

Antigens unique to the tumor and not found on normal cells

Question 32

Tumor Associated Antigens

Answer 32

Antigens present on a tumor and a limited number of normal cells

These antigens are present in a higher amount on tumors than normal cells

Or, expression of developmental proteins on adult tissue for that specific tissue type

Question 33

Useful tumor antigen criteria

Answer 33

Released only by tumor tissue
Specific for a tumor type (breast vs lung vs colon, etc.)
Has a direct relationship to (on the surface of) a tumor cell
Present in all patients with that type of tumor

Question 34

How Tumor Specific Antigens arise

Answer 34

A silent gene is activated resulting in the synthesis of a new protein

Point mutation within an already active gene that alters the structure of the expressed protein

An alteration in protein structure that exposes a previously sequestered epitope

Question 35

Examples of tumor specific antigens

Answer 35

Galactin 9 is present in about half of Hodgkin’s patients

Protein 17-1A is specific to human carcinoma cells

MAGE 1-3 are melanoma antigens

Question 36

Tumor specific therapy

Answer 36

Therapies can be designed once tumor specific antigens are identified so that only cancer cells are attacked rather than all rapidly proliferating cells like in traditional chemotherapy

Question 37

Immunotherapy

Answer 37

Stimulates the patient’s immune system to fight cancer

Isn’t tumor specific and thus can be helpful against heterogeneous tumors

Question 38

Two types of Immunotherapy

Answer 38

Passive and Active

Question 39

Passive Immunotherapy

Answer 39

Infusion of antibodies, cytokines, or immune cells to patients who may not be able to mount an immune response

Graft or transplant rejection (GVHD graft vs host disease) is a big barrier to this therapy since the infusion is recognized as non-self

Question 40

Allogenic Adoptive T cell therapy

Answer 40

A form of passive Immune therapy

T cells from an allogenic donor (immune incompatible) are immunized in culture against a tumor. The patient undergoes immune suppression and is injected with the transplanted T cells

The allogenic T cells can also be engineered with an apoptosis switch so that if graft rejection occurs the patient takes a special drug that kills all the donor T cells to prevent GVH Disease

Question 41

Autologus Adoptive T-cell Therapy

Answer 41

The patients own T cells are harvested, exposed to cancer antigens in culture, expanded with Interleukin 2 IL-2 cytokine to increase immune response, and injected back into the patient

Question 42

Monoclonal antibodies (passive)

Answer 42

(Passive) mAb circulates until it binds to the target cancer antigen

Question 43

Antibody conjugates or immunotoxins (passive)

Answer 43

Antibodies that are conjugated to toxins or radioisotopes

Kill cancer cells (that they bind to) while leaving adjacent cells intact

Question 44

Active Immunotherapy

Answer 44

Patients are treated so that their immune system is stimulated to respond to their tumors

Question 45

Cancer Vaccines

Answer 45

Developed against specific viruses known to cause cancer such as HPV

Limited success vaccinating with the patients’ own cancer cell lysates as an individualized treatment

Question 46

How is IHC useful in Cancer diagnosis and treatment?

Answer 46

1. Categorize undifferentiated tumors based on known surface marker staining
2. Determine the site of metastatic origin by staining for cell specific/tumor antigens to find which organ the foreign mass came from (ex: breast cells in your lung)
3. Detecting molecules that have prognostic or therapeutic significance (ex: what type of breast cancer markers you have so we give you the right drug/are able to tell you how bad it is and chance of survival)