Lecture 3: Cancer and the Immune System Flashcards
What is tumor immunology?
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
Normal cells growth and development
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
What are protooncogenes?
Regulatory genes that promote cell division
What are tumor suppressor genes?
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
Drawbacks of tumors’ similarity to normal cells
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
What are the two tumor varieties?
Benign and malignant
Benign tumors
Possess a capsule that surrounds the abnormal growth
These masses lack the ability to invade other tissues
Malignant tumors
Do not possess a capsule
Are able to invade other tissues and disrupt bodily functions to the point of causing death
Metastasis
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
Conversion of normal cells to malignant cells is a:
Process
That occurs slowly over time and includes 3 phases
What are the 3 stages of conversion to cancer?
Induction Phase
In situ Phase
Invasion phase
Induction Phase
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
In situ Phase
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
Invasion Phase
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
Dysplastic cells
Abnormal cells that are the precursors to neoplasms
Monoclonal origin, heterogeneous proliferation, and immune evasion of cancer
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
Detection issues as a result of cancer mutations
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
Anaplastic
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
TNM System
This is the tumor classification system
T size of the primary tumor
N involvement of adjacent lymph nodes
M detection of metastasis
Immunosurveillance
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
Immunoediting
The actual response to immune pressure on cancer cells that results in selection of the most resilient tumor cells
Three phases of immunoediting
Elimination
Equilibrium
Escape
Elimination
The immune system eradicates easily detected tumor cells, but a few remain due to advantages obtained through mutations. This is a form of selection.
Equilibrium
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.
Escape
The tumor grows and expands completely unchecked as a majority of the cells are immune resistant.
HSP and immuno-detection
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
MHC and immuno-detection
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)
Tumor growth rate as evasion
Some tumors simply proliferate too quickly to be kept in check by the immune system, even if some cells are being regularly destroyed.
PD1/PDL1 pathway evasion
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
2 Types of Tumor antigens
Tumor Specific Antigens
Tumor Associated Antigens
Tumor Specific Antigens
Antigens unique to the tumor and not found on normal cells
Tumor Associated Antigens
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
Useful tumor antigen criteria
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
How Tumor Specific Antigens arise
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
Examples of tumor specific antigens
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
Tumor specific therapy
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
Immunotherapy
Stimulates the patient’s immune system to fight cancer
Isn’t tumor specific and thus can be helpful against heterogeneous tumors
Two types of Immunotherapy
Passive and Active
Passive Immunotherapy
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
Allogenic Adoptive T cell therapy
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
Autologus Adoptive T-cell Therapy
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
Monoclonal antibodies (passive)
(Passive) mAb circulates until it binds to the target cancer antigen
Antibody conjugates or immunotoxins (passive)
Antibodies that are conjugated to toxins or radioisotopes
Kill cancer cells (that they bind to) while leaving adjacent cells intact
Active Immunotherapy
Patients are treated so that their immune system is stimulated to respond to their tumors
Cancer Vaccines
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
How is IHC useful in Cancer diagnosis and treatment?
- Categorize undifferentiated tumors based on known surface marker staining
- 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)
- 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)
