Cancer Immunology Flashcards
(85 cards)
1
Q
LO
A
- Explain how the immune system is able to detect cancer cells
- Describe the ways in which cancer cells can evade the immune system
- Identify key strategies used in cancer immunotherapy and describe their mechanisms of action
2
Q
Lecture topics
A
- What is cancer and how does it arise?
- What is the role of the immune system in cancer?
- How do cancers survive when the immune system is able to detect them?
- How do we overcome immune evasion and tumour immunosuppression?
3
Q
What is cancer and how is it characterised?
A
- Change behaviour – no longer obey signals
- Uncontrolled division of cells
- Need multiple mutations along these pathways to become malignant
4
Q
Tell me the stages to how normal cells transform from normal cells to viral oncogenes or cellular oncogenes
A
5
Q
What are proto-oncogenes and what are they involved in?
A
Proto-oncogenes are a group of normal genes in a cell.
They contain the necessary information for your body to make the proteins responsible for:
- stimulating cell division.
- inhibiting cell differentiation
- preventing apoptosis (cell death)
6
Q
What are some genes involved in tumorigenesis?
A
7
Q
What are the main stages of tumour development?
A
- Normal epithelium
- Hyperproliferative epithelium
- Early adenoma
- Intermediate adenoma
- Late adenoma
- Carcinoma
- Metastasis (when cancerous cells break away from the main tumour, enter the blood stream and spread through the vasculature system to other parts of the body)
Adenoma: a type of non-cancerous tumour or benign that mat affect various organs
These are the stages the cells go through to turn from benign –> malignant
8
Q
Why are cancerous cells different to other cells, what do they do when in the body?
A
- Escape normal intercellular communication
- Allow for rapid growth
- Increased mobility of cells
- Invade tissues
- Metastasis
- Evade the immune system
9
Q
What are the two main roles of the immune system in cancer?
Tell me about each one and what it entails
A
Immunosurveillance- One of the functions of the immune system is to identify and kill tumour cells
Immunoediting- Cancers which come to medical attention are only those that have managed to evade the immune system
10
Q
What is some evidence for immunosurveillance?
A
- The high frequency of cancers in immunosuppressed patients
a. Extremes of age
b. Primary and secondary immunodeficiency
c. Immunosuppressive drugs (transplants) - Increased incidence of tumours in neonatal thymectomised and immunocompromised mice
- Tumour-specific T cells and antibodies are found in cancer patients
11
Q
Can there be spontaneous immunity without infection?
A
yes
Transplant (immunosuppressed) patients are also at increased risk of cancer
12
Q
Tell me about the ability of many transplantable (chemically induced) tumours in generating an immune response…
A
They are highly immunogenic
Tumour antigens have been defined
13
Q
Patients with what present have an improved prognosis?
A
Tumour Infiltrating Lymphocytes (TIL)
14
Q
Where does sponanteous regression occur?
A
Melanoma, breast and lung cancer
15
Q
How does the immune system recognise tumour cells?
A
Tumour associated antigens
Tumour specific antigens
16
Q
What are some examples of associated antigens in cancer and what types of cancer are they associated with?
A
Tyrosinase, MAGE-1 and gp100 - melanoma
NYESO-1 – colorectal cancer
PSA – prostate cancer
HER2 – breast cancer
17
Q
What can tumour associated antigens lead to and why is this the case?
A
Can lead to cross-reactive responses as antigen also expressed in normal cells
18
Q
What is Vitiligo and what is it used as?
A
Anti-melanoma responses recognise normal melanocytes as ‘foreign’ and kill them = vitiligo
Vitiligo used as a marker for response to therapy
19
Q
What are Carcino-embryonic antigens (CEA)?
What are they expressed by?
When do they increase/ decreases?
A
Carcino-embryonic antigen (CEA)
Expressed by some cancers (esp. colorectal, pancreatic, gastric, breast, lung)
Generally not expressed by normal tissues
Increases with recurrence
Decreases with cure and in some nonmalignant conditions (e.g., chronic cirrhosis, inflammatory diseases of GIT and lung).
20
Q
Despite the presence of an anti-tumour immune response, many are not eradicated.
What tumours are selected and what immune process begins?
A
Despite the presence of an anti-tumour immune response many are not eradicated
Tumours with low antigenicity selected
Immune editing - Loss of antigenicity due to selective pressure from immune response
21
Q
What are the three processes involved in immune editing?
A
- Elimination
- Equilibrium
- Escape
22
Q
What does immune editing lead to?
A
Leads to immune evasion
Hallmark of cancer progression
23
Q
How does cancer avoid immune destruction in the emerging hallmarks of cancer?
A
- Alter tumour cell antigenicity
- Decrease antigen presentation
- Immunosuppression
- Tumour microenvironment architecture
24
Q
What is the tumour progression- immune evasion mechanism?
A
25
What processes with the tumour lead to the epitope being lost or preserved?
26
When reducing antigen presentation, what is there a selective advantage with?
Reduced MHC class I expression
27
What does reduced antigen presentation occur in, give some examples with incidences
Occurs in many cancers
* **Associated with more aggressive and metastatic tumours**
* \>75% of thyroid cancer
* 50% of aggressive breast cancer
* and 40% of lung cancer have loss of MHC class I expression
28
What does the MHC class I processing pathway downregulate?
**TAP**
**b2m**
**MHC allele**
29
What does the MHC class I processing pathway prevent recognition by?
What are they possibly activated by?
All prevent recogntion by CD8+ T cells
Possible activation of NK cells due to reduced MHC class I
30
The pre-clinical models for cancer immunoediting
31
What is there a correlation between in melanoma?
T cell transcripts and chemokines
AND
Type 1 interferon and the pro-inflammatory phenotype
32
What is the role of type 1 interferons within the immune system?
They play a key role in driving an **antiviral state in non-immune cells**
Also involved in the **antiviral immune response** through...
* inhibiting viral replication in infected cells in the innate stage of the immune response
* Activating and enhancing antigen presentation in early immune response
* Triggering the adaptive immune response through direct and indirect action on T and B cells that make up the memory response
**NOTE:** innate or nonspecific immunity is the defence system with which you were born with. it protects you against all antigens
33
What is **cytosolic DNA sensing** done by and what process does this drive?
Cytosolic DNA sensing by **DCs via STING** drives a **‘pro-inflammatory’ phenotype**
34
What does the 'pro-inflammatory' phenotype lead to the production of?
Type 1 interferons
35
What process do macrophages go through which induces the expression of pro-inflammaotry cytokines and also reduces phagocytic efficiency?
**Glycation**
This process upregulates mRNA expression of the following pro-inflammaotry cytokines in M1 and M2 macrophages..
* *M1:** IL-1beta, TNF-alpha and IL-8
* *M2:** TNF-alpha and IL-8, IL-10
36
What are the two different types of macrophages in immunology and what are each of them involved in?
M1/M2 describes the two major and opposing activites of macrophages
M1: activity inhibits cell proliferation and causes tissue damage
M2: activity promotes cell proliferation and tissue repair
37
What are the cytokines produces by both the M1 and M2 macrophage?
38
What is critical to anti-tumour CD8 responses?
***Batf3*** dependent CD103+ DCs
39
If antigens are present in at least some tumours, why does immunosurveillance sometimes fail?
1. Lack of inflammatory infiltrate (TILhi is good)
2. And/ or local suppression
40
Tumour-reactive T cells in the periphery of patients with melanoma do not correlate with survival. 'Pro-inflammatory' tumour environment predicts for adaptive response to immunotherapy. Give to examples which compete with one another...
What cancers is this true for?
e.g., **TILhi Vs TILIo**
This is true for...
* melanoma
* ovarian cancer
* colorectal carcinoma
* lung
* bladder
* prostate
* renal
* oesophageal cancers
* etc.
41
Is the tumour environment immunosuppressive?
yes
42
What is the immunosuppressive environment of the tumour environment driven in part by?
CD8+ T cells
43
Tell me what a tissue microenvironment is and what is is comprised of in a developing tumour
A tissue microenvironment of developing tumor is comprised of **proliferating tumor cells, the tumor stroma, blood vessels, infiltrating inflammatory cells and a variety of associated tissue cells.**
It is a unique environment that emerges in the course of tumor progression as a result of its interactions with the host.
44
What does the tumour microenvironment prevent?
Infiltrating T cells from working properly and induce 'exhaustion' phenotype in infiltrating T cells
45
What is T-cell exhaustion characterised by?
T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells.
46
Tumour microenvironment...
47
During immunosuppression there is a recruitment of immunosuppressive cells, what are these cells?
* **regulatory T cells** (Tregs)- CD4 T cells that express FoxP3
* General immunosuppression of antigen-specific
* See accumulation of Tregs in tumour over time
* Recruited by chemokine **CCL22** secreted by tumour cells (CCR4 on Tregs)
48
In the immunosuppressive environment tell me the following involved...
Cells?
Soluble?
Interaction?
**Cells:** Tregs, Tumour Associated Macrophages (TAM), Cancer Associated Fibroblasts (CAF)
**Soluble:** TGF-b, IL-10, VEGF
**Interaction:** PD-1/PD-L1, CTLA-4, TIM-3, LAG3
49
Tell me about TAMs (Tumour-associated macrophages)
**TAM (tumour-associated macrophage)**
M2 type macrophage = decrease inflammation and promote tissue repair (IL-10, TGF-b)
50
Tell me about **CAF (cancer-associated fibroblasts)**
**CAF (cancer-associated fibroblasts)**
Develop from fibroblasts in the presence of TGF-b
Stimulate angiogenesis and block T cells from attacking tumour
51
TAM cells express a M2-phenotype, what do their presence indicate?
Indicate a poor prognosis
There is also notably high **M2/M1 ratio**
52
What cytokines promote M2?
**IL-4, IL-13, IL-10 and GM-CSF** promote M2
53
What do M2 macrophages promote aspects of?
M2 promote aspects of **tumourigenesis and hinder immunity** via IL-10, TGF-b and recruitment of Tregs (CCL22)
54
What cytokines promote M1?
**GM-CSF, IFN-g, TLR and STING agonists** promote M1
55
What do M1 macrophages promote immunity via
M1 promote immunity via **IL-1, IL-12, cytotoxicity etc**
56
Roles of TAMs in the immune system
57
Whats the role of **stromal cells** in cancer?
* cells that make up a certain type of connective tissue (supporting tissue that surrounds other tissues and organs)
* development of tumour microenvironment
* metastasis
* immune infiltration
* inflammation
*
58
What is the role of immunosuppressive cytokines?
TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
reciprocal relationship between T cells and TGFbeta
59
Give an example of a tumour intrinsic factor
What does it prevent?
Melanoma-intrinsic Beta-catenin signalling
It prevents anti-tumour immunity
60
Tell me the role of the tumour intrinsic factor **beta-catenin** in melanoma
Active beta-catenin signalling leads to CAT activation which binds to ATF3
ATF3 then suppresses CCL4
In the absence of beta-catenin there is an activation of CCL4
61
The tumour environment is often T cell suppressive
62
How cna we encourage a 'pro-inflammatory' tumour environment?
**Agonists/inflammation**
* Either directly e.g., TLR9/type I IFN/STING agonists
**Or indirectly**
* e.g., radiation
**Provide more T cells by adoptive transfer**
63
What are the reasons for immune evasion in T cell-poor tumour vs T cell-inflamed tumour
64
What are the therapeutic interventions for T cell-poor tumours vs T cell-inflamed tumour
65
Tell me about **William Coley (1862-1936) – a pioneer in cancer immunity**
* Bone surgeon at Memorial Sloan Kettering New York
* As a new doctor lost a 17-year-old patient to sarcoma within 10 weeks of diagnosis
* Diedier (1725) – patients with syphilis have reduced rates of cancer.
* Busch (1867) – Strep infection triggered spontaneous tumour regression.
* In fact, 47 separate cases where infection associated with regression.
* In 1891 injected a patient with Strep – tumour regressed.
* Moved to dead bacteria to decrease mortality. Cure rate of \>10%
66
What are the two types of cancer immunotherapies?
**Active** and **passive** therapies
67
Tell me about **active** cancer immunotherapies
Active rely on an active immune response
Use of vaccine approaches or cytokines to stimulate immune cells
68
Tell me about **passive** cancer immunotherapies
Passive does not require an active immune system
Antibodies or immune cells given to patients
69
For active immunotherapy, give examples for the following...
* cytokines, biological adjuvants
* innate agonists
Tell me a generalisation about them
Cytokines
Biological adjuvants
* **GM-CSF**
* **IL-2**
* **TNF-a**
Innate agonists
* **TLR**
* **STING**
Can cause toxicities
Not very effective on their own
70
Tell me about STING agonism and the STING pathway
NOTE: STING (Stimulator or interferon genes) and is a TM protein
* innate immune pathway
* senses cytosolic DNA
* triggered by cGAMP synthases binding directly to DNA
71
provide example of active immunotherapies
**Vaccines**
* Prophylactic and therapeutic
**HPV vaccine (Cervical cancer)**
* 3000 new cases/year and 1/3 will die from disease
* Most common cancer in under 35s
* \>99% of cancer is induced by HPV infection
* Cervarix vaccine introduced 2008 – Gardasil in 2012
* High risk HPV type 16 and 18 accounts for 70%
72
Have therapeutic vaccine succeeded in the context of cancer as of yet?
No
73
What do therapeutic vaccine target, immunise with and also monitor?
**Target** tumour antigens
**Immunise** with:
* peptides
* recombinant viruses
* DNA
* dendritic cells
**Monitor** T cell response
74
What do Cell based vaccines (DC) use?
* Use DC to take up and present tumour antigens in an immunogenic way
* Approved in 2010 as a vaccine for prostate cancer (PSA) together with biological adjuvant (GMCSF) – not on NHS
* Many ongoing trials to use DC vaccines in cancer
75
What is the general steps to the process of how cell based vaccines work?
76
Whats a **Neoantigen**?
A new protein that forms on cancer cells when certain mutations occur in tumour DNA
These play an important role in helping the body make an immune response against cancer cells
They are used in vaccines and other types of immunetherapy that are being studied in the treatment of different types of cancer
77
Tellme about tumour neoantigens
Neoantigen identification
Antigen processing modulation
* Tumour specific mutations provide targets for T cells
* Link between mutational load and response to checkpoint blockade
Neoantigen identification
78
What is used to generate anti-tumour response?
Immunise/vaccinate identified tumour specific neoantigens
79
Give an example of passive immunotherapy
Adoptive Cell therapy
CAR T cell therapy
80
Tell me a bit about adoptive cell therapy and CAR T cell therapy
Stem cell transplantation used in leukaemia lymphoma
TcR and CAR T cells
Relatively new therapy – very effective in some cancers
81
Whats the process called where neoantigens are used to expand T cells?
Adoptive cell transfer, ACT
82
Tell me about the **chimeric receptors** with CAR T cells
Fusion of a single chain variable fragment that recognises a tumour specific antigen (e.g., CD19) with an intracellular signalling module that include CD3z
83
What cancer is CAR T cells also involved in?
AML (acute lymphoblastic leukaemia)
84
What new antibody therapies have recently been developed?
* Targeting inhibitory interactions such as PD-1/PD-L1
* Disease markers specific for target cells e.g. Rituximab – CD20 on mature B cells
* Learn more in next lectures…
85
**Summary**
* **The immune system recognises and targets cancer cells**
* **Cancers can evade the immune system and establish an immunosuppressive microenvironment**
* **Immunotherapy can activate the immune response and overcome these immunosuppressive mechanisms**
