L12 Cancer and the Immune System & Immunotherapy Flashcards
does an individual need one or two copies of the gene to be knocked out from birth in order to be at higher risk for cancer?
two copies need to be knocked out as there are normally two copies, if one copy is present it can ‘compensate’ if one copy is knocked out.
% cancers caused by environmental factors?
approximately 80%
What are Mut-driver genes?
These are genes that contribute to cancer
What is a driver mutation?
A change in a gene/protein that gives a cancer cell a fundamental growth advantage for its neoplastic transformation.
Define cancer:
malignant transformation of cells
Where do carcinomas arise from?
From the endoderm and ectoderm
Carcinomas are epithelial cell cancers
Give an example of a carcinoma
- Breast cancer
- Colon cancer
What is leukaemia?
Leukaemia is cancer of the blood or bone marrow, involving the abnormal increase of immature white blood cells called ‘blasts’
What is lymphoma?
A tumour in lymphoid tissue, bone marrow, lymph nodes
what is melanoma?
cancer involving the melanocytes of the skin
which cells are involved in acute lymphocytic leukemia?
immature abnormal B cells (blasts)
Which parts of the body are affected by ALL?
Bone marrow and blood affected
Also common for liver, spleen or lymph nodes to become enlarged
What are the clinical signs of ALL?
Anaemia, low white blood cell count, weight loss, malaise, fatigue
define thrombocytopenia
Absence of functional granulocytes
Blood platelet count is low
Give examples of tumour associated antigens (TAAs)
CD19, CD20, CD22
Define stem cells
at cell division, one or both daughter cells remain undifferentiated with the ability to give rise to another stem cell with the same capacity to differentiate and produce cells in each organ.
What is the cancer stem cell hypothesis?
That tumour cells/cancer cells can self-renew. They can produce the bulk of cells within a tumour, may only compose 1% of the actual tumour.
what is the difference between cancer stem cells and normal stem cells?
cancer stem cells have chemo-resistance, tumourigenic and metastatic activities.
Why are cancer stem cells a target for treatment?
They are thought to be resistant to most therapies, so when the tumour is reduced/ bulk is destroyed, the CSCs can continue to self-renew and regrow the tumour.
What are tumour associated antigens (TAAs)?
self-proteins which are minimally expressed by healthy tissues but constitutively overexpressed in cancer cells as a result of their malignant profile
Give examples of TAAs
VEGF, HER2, hTERT, CEA, CD19
Tumour-specific antigens (TSAs) definition:
Exclusively restricted to tumours, not found on healthy tissues. Caused by malignant mutations or the expression of viral antigens
what antigen is overexpressed in the vast majority of colon cancers?
CEA
what is CEA
Expressed in fetal development, an oncofetal protein
is CEA presented before or after thymic education?
before thymic education, perceived as foreign as a result
what are oncofetal antigens?
Can be expressed at high levels in some cancers. not normally expressed in healthy adult tissue, expressed during fetal development.
Are CEA and other oncofetal proteins perceived as foreign by the immune system?
Yes, they are recognised as non-self antigens.
α-fetoprotein is expressed in which cancer?
Liver cancer
Which cancer type(s) is EBV linked to?
Burkitt’s lymphoma and nasopharyngeal carcinoma
Which cancer is H. pylori infection linked with?
Stomach cancer
what cancer is HPV linked to
strains HPV 16 and 18 are linked to cervical cancer
Which cells are responsible for immunity to tumours?
macrophages, dendritic cells, B and T cells
What do CD8+ T cells recognise in a tumour cell?
Tumour associated antigens
What do natural killer cells recognise in tumour cells?
They recognise decreased or lack of MHC class I on the surface of the tumour cell.
what does the presence of IFN-gamma and IL-2 cytokines on the margin of tumours indicate?
Tumoricidial activity, good sign - tumour being destroyed
what does the presence of macrophages in the vicinity of a tumour often indicate?
tumour regression
what do macrophages produce to trigger programmed cell death?
TNF-alpha and lytic enzymes
populations at higher risk of tumor development
young, old, immunosupressed
what is sarcoma a cancer of?
cancer of connective tissues
what do CTLs recognize on tumors in relation to MHC class?
they recognize cancer peptides which are blocking the MHC class I and induce apoptosis
what do natural killer cells recognise on tumor cells in relation to MHC class?
they recognsie the absence of MHC class I
what immune cell removes apoptotic bodies?
macrophages
Describe the mechanism of how the cancer cell presents its cancer antigen
The cancer cell loads tumour-derived peptides into a proteasome, ships it to the ER, it is then loaded onto MHC class I
what immune cells can tumor cells recruit to aid the evasion of the immune response?
they can recruit T reg cells and certain myeloid cells to suppress the immune response to the tumor.
Describe PDL1 and PD1 interaction and T cell deactivation
PD1 receptors are located on T cells. They bind PDL1. This is normally an immunosuppressive regulatory mechanism and suppresses T cell activity. This can be hijacked by tumour cells to suppress the immune system and evade it.
What is anergy?
An immunologic tolerance characterised by the failure to mount a full immune response against the tumour.
Role of MHC presentation in anergy to form the immunosuppressive environment?
Failure of cancer cells to present cancer antigens due to down-regulation of MHC Class I
Role of APCs in anergy for immunosuppressive environment?
Cannot efficiently present cancer antigens to CD4+ and CD8+ lymphocytes
What do tumour cells release in hypoxic conditions to suppress the immune system?
Adenosine, specifically suppresses the activation of T cells
What immunosuppressive cytokines do tumour cells secrete?
IL-10, TGF-beta
What antigen does Trastuzumab (Herceptin) target?
HER2, over-expressed in some breast cancers
what is the function of immune checkpoints and what do they do once an infection has been controlled?
immune checkpoints control the immune response, they downregulate the response if it is controlled.
how do immunotherapy drugs called immune checkpoint inhibitors work?
They block the immune checkpoint proteins from binding to the partner proteins, which prevents “off” signal being transmitted. This allows T cells and APCs to remain active and attach to/ kill cancer cells.
What is CAR-T cell therapy?
genetically edited T cells which are manipulated to fight the disease.
what are chimeric antigen receptors?
CARS are molecules genetically engineered into a polyclonal T cell population giving the T cells the ability to recognise tumor associated antigens.
what components of the immune system does the CAR-T cell therapy employ?
The specificity of an antibody and the cytotoxic ability of a T cell
how are the CAR-T cells introduced to the patient?
retrovirus transposition
scFV antibody function in CAR-T cell therapy?
binds the target antigen
CD28 and CD3zeta function in CAR-T cells?
Send signals to activate T cells
what is the main issue associated with allogenic T cells for use in CAR-T cells?
potential for GVHD due to specificity of individual MHC
What is a cytokine-related issue associated with CAR-T cell therapy?
Cytokine Release Syndrome (CRS)
Potential solution for CRS?
Infuse monoclonal antibodies into the patient to neutralise the effects of the overproduced cytokines
why is dendritic cell therapy for cancer thought to not be as successful as CAR-T cell therapy?
this is because the antigen presenting process is impaired in the immunosuppressive tumour environment
