Cancers Flashcards
what cells consists within tumour microenvironment (TME)?
cancer stem cells
cancer cell
endothelial cells
pericyte
cancer-associated fibroblasts
invasive cancer cells
immune inflammatory cells (ICs)
how do the different cells in the TME communicate?
secreted growth factors
enzymes
and cytokines
where are immune cells derived from?
haemolytic stem cells (HSC)
from the bone marrow
what do Hematopoietic stem cells (HSC) form?
- myeloid progenitor cells - passive immune cells
- lymphoid progenitor cells - adaptive immune cells
what are myeloid progenitor cells?
macrophages
what are lymphoid progenitor cells?
CD8 T cells
CD4 T cells
memory cells
plasma cells
What is immune tolerance?
Refers to the immune system’s state of unresponsiveness to substances or tissues that would otherwise trigger an immune response.
What is Central tolerance?
- occurs for premature immune cells, known as thymocytes
- strongly self reactive immature lymphocytes deleted
- increase affinity binding = cell death
What is Peripheral tolerance?
- apoptosis of lymphocytes that recognise self antigens in the periphery
- suppression of responses by regulatory T cells (Tregs)
what is immune surveillance theory?
constantly monitoring the body for the appearance of tumour cells, and that the majority of these abnormal cells are destroyed by the immune system before giving rise to clinically manifest tumours.
How does the immune system identifies tumour cells?
using neoantigens
how are neoantigens formed?
mutations in the cancer genome = tumour antigens
how do T cells get activated?
T cell receptor (TCR) on naive T cell binds to the antigen presented on the MHC (1 or 2) on the antigen presenting cells (APCs) = primary signalling
a second costimulatory signal is required for full activation of T cells
what is MHC 1/2?
human leukocyte antigen
whats an example of APC?
antigen presenting cells
dendrite
how is a second co-stimulation signal mediated?
tightly controlled interplay of stimulatory/inhibitory receptor and ligand pairs also known as IMMUNE CHECKPOINTS
what is an example of a second co-stimulation signal?
CD28 signal
what are immune checkpoints?
receptors/ligand pairs that activate full T cell activation thru a second co-stimulatory signal
what is CTLA4?
- member of CD28 receptor family on T cells
- out competes with CD28 ligands for B7-1 on the APC due having a higher affinity with CTLA4
- inhibits immune response at the priming phase of T cell activation
describe CTLA4 blockade for cancer therapy
anti-CTLA4 - ipilimumab
prevents its interaction with B7 ligands.
what are the side effects of ipilimumab?
skin lesions (rash/ vitiligo)
colitis
hepatitis/ hypophysitis/ thyroiditis
dose-dependent irAE’s
explain the mechanism of anti-CTLA4?
what is PD1?
IMMUNE CHECKPOINT for activated t cells
inhibitory function mediated by the tyrosine phosphatase SHP-2, which dephosphorylates signalling molecules downstream the TCR
What does PD1 bind to ?
PD-L1
PD-L2
what does inflammation induced PD-L1 expression on B cells cause?
PD1 T cell exhaustion = inhibiting CD8 response
name some IMMUNE CHECKPOINTS?
activated T cell - PD1
naive T cells - CTLA4
how is PD-L1 expressed?
- TCR binds to the antigen in the MHC
- binding induces IFN-y expression
- IFN-y recognition via cancer cell receptors
- IFN-y receptors signals to JAK1/2 receptors
- JAK 1/2 receptors induces PD-L1
- blocks activated T cells
what are examples of anti-PDL1?
pembrolizumab - melanoma
nivolumab
what is pembrolizumab?
anti-PDL1 antibody for mismatch repair deficient cancer (dMMR) for solid tumours
explain anti-PDL1 MOA ?
whats the difference between anti-CTLA4 and anti-PDL1?
what are mechanisms of resistance to immune checkpoint inhibitors?
- primary - pt does not respond
- acquired
- intrinsic - alter processed related to (immune recognition/cell signaling/gene expression/DNA damage response)
- extrinsic - Resistance occurs external to tumor cells throughout the T-cell activation process
what is immunoediting?
A dynamic process involving the immune system’s recognition, shaping, and elimination of cancer cells, comprising three phases: elimination, equilibrium, and escape.
high tumour intra-heterogeneity can cause what?
- Treatment resistants
- Metastisis
- Tumour recurrance
what can cause resistance to IMMUNE CHECKPOINT BLOCKADE?
- immune suppressive cells w/ inhibitory cytokines = undermine anti-tumour response
- Tregs/ myeloid derived suppressive cells (MDSCs) tumour infiltration - M2 macrophages = promote tumour progression
- VEGF high levels in PD1 non-responding patients
- impaired priming of naive T cells
- tumour mutations = loss of HLA expression
- patients who respond poorly too aPD1 therapy = less tumour associated memory T cells
- wnt/b-catenin signalling
what are immune suppressive cells w/ inhibitory cytokines ?
- Tregs
- myeloid derived suppressive cells (MDSCs) tumour infiltration
what cell signalling pathways influence immune response?
- hyper-activation of MAPK signalling = less TILs recruitment thru VEGF expression
- PTEN deletion = decrease cytotoxic T cell activity = resistance to aPD1
- WNT/B-catenin ICB resistance
what is cancer screening?
testing healthy people for signs of the disease at an early age to prevent cancer developing and better survival chances
what are the two types of cancer screening?
- opportunistic - symptoms displayed and screened by doctors
- population based - cohort of people to screen (e.g. women aged >60yrs old)
what does early detection of cancer allow?
allow better treatment plans with a high survival rate
what makes a cancer suitable for screening?
- effective tests (high specificity and sensitivity)
- test should be acceptable to the population (ppls morals n ethics)
- healthcare system can cope with the downstream impact of positive results
- must increase survival
why must cancer screening be highly specific and sensitive?
highly specific - low chance of a false positive
highly sensitive - low chance of getting a false negative
THEREFORE IMPORTANT
what do screening tests include?
Physical examination
e.g. checking skin for moles
▪Laboratory tests
e.g. measuring levels of PSA, examining cervical tissue samples
▪Imaging procedures
e.g. Breast mammography
▪Genetic Tests
e.g. BRCA testing
who should we be screening?
Usually screening focuses on people at increased risk of a disease due to:
▪ Family history / genetic mutations
e.g BRCA testing
▪ Exposure to cancer-causing agents
e.g. lung cancer for smokers
▪ Age
e.g. elderly
why do we have to be careful to screen elderly?
risk-benefit ratio with treatments
may not be clinically sustainable
what are the pros and cons of screening?
pros:
-better outcome
-less radical therapy needed
-reassurance for pts with negative results
-psychological benefit
-less complex therapies=cheaper
cons:
-cost of screening
-risk of false positives
-longer morbidity if prognosis is unaltered
describe uk’s breast cancer screening programs
offered to 50-70 yr old; women.
every 3 years
high risk pts (family history/prior cancer) will be offered earlier screening
uses X-ray tests - mammogram
what is the chance of women developing breast cancer ?
clinically 1 in 7 women
what was the main risk of breast cancer screening?
increased risk of over-diagnosis - screening picks up cancers that would have never manifested clinically, thus skewing the survival rates
what does over-diagnosis mean?
screening picks up cancers that would have never manifested clinically, thus skewing the survival rates
describe uk’s cervical cancer screening programs
25-64 yrs old
every 3 yrs til 49yrs old, then every 5 years
Small sample of cells taken from the cervix. Sample is checked for high risk human papillomavirus (HPV) that can cause changes to the cells of the cervix.
If these types of HPV are not found, no further tests are undertaken.
If these types of HPV are found, the sample is then checked (using liquid based cytology) for any changes in the cells of the cervix. If changes detected, patient invited back for a colposcopy
how has cervical cancer screening helped?
mortality rates decreased by 70%
incidence to reduce further due to HPV vaccines
what is a main cause of cervical cancer?
HPV virus
what can we do to prevent cervical cancer?
vaccine against HPV
why are cervical cancer screening programs not <25 or >65 yrs old?
If you’re <25
▪ cervical cancer is very rare in people under 25
▪ it might lead to having treatment you do not need – abnormal cell changes often go back to normal in younger women
If you’re 65 or older
▪ You’ll usually stop being invited for screening once you turn 65. This is because it’s very unlikely that you’ll get cervical cancer.
▪ Only be invited again if 1 of your last 3 tests was abnormal.
describe uk’s bowel cancer screening programs
bowel scope no longer offered
offered to 60-74 yrs old, at specific antibody home test kit every 2 years
hoping to lower bowel screening age to 50 in the future
what kits are used for bowel cancer screening?
faecal occult blood test (gFOBT) less accurate = less used
faecal immunochemical test (FIT) - more accurate = easier to use
what do the specific antibodies in the human blood detect?
detect human blood in the stool
what are the statistics of bowel screening?
2 out 100 will be positive and offered a colonoscopy
describe uk’s prostate cancer screening programs
not offered but >50yrs old request tests to be done
not ideal as incidence is increasing due to an ageing population
describe uk’s lung cancer screening programs
lung health checks trialled - pts determined to be high risk of lung cancer will be invited for CT screening
what screening programs do we have ?
-breast
-cervical
-prostate
-bowel
(-lung)
what screening programs may we have in the future?
(-lung)
-skin
-ovary
-thyriod
-endrometrium
OTC screening kits
genetic screening for all common cancer - breast/prostate/bowel/ovary
how can pharmacists aid cancer screening?
- encourage people to attend/undertake screening
- provide information/reassurance about the screening process
what are the barriers for people to not attend to cervical screening?
frequent non attenders:
- ethnic minorities
- women over 50 and 25-29
- lesbian/bisexual women
- lower socio-economic groups
do not attend due to:
- embarrassed to have a smear test
- worried of the result
- concerned about the procedure
- access to screening and appointment times
- don’t think they are at risk
- unaware of screening
