Neoplasia 2 Flashcards
Examples of hallmarks of cancer
avoiding immune destruction, polymorphic microbiomes, tumour-promoting inflammation
What are the 3 roles of the immune system in preventing tumours?
- eliminating/suppressing viral infections to prevent virus-induced tumours
- prompt elimination of pathogens and resolution of inflammation to prevent an inflammatory environment conducive to tumorigenesis
- immune surveillance - identifying and eliminating tumour cells on basis of tumour-specific antigens
Why can the relationship between the immune system and cancer be considered paradoxical?
immune system can eliminate (immune surveillance) but also promote cancer (inflammatory environment promotes tumorigenesis)
Immune surveillance definition
the immune system identifies and eliminates cancerous/precancerous cells before they can cause harm
Which mechanisms eliminate cancer cells during immune surveillance?
DNA repair (p53), apoptosis, immune response (e.g. phagocytosis)
What is the term used to describe tumour cells that are identified and eliminated by immunosurveillance?
highly immunogenic tumour cell
What is meant by a poorly immunogenic tumour cell?
a malignant cell with acquired gene mutations allowing them to evade immunosurveillance resulting in cancer
What is cancer immunoediting?
an extrinsic tumour suppressor mechanism that engages after cellular transformation and the failure of intrinsic tumour suppressor mechanisms
What are the intrinsic tumour suppressor mechanisms?
repair, senescence (biological ageing), apoptosis
What are the 3 phases of cancer immunoediting?
elimination, equilibrium, escape
What is the elimination phase of cancer immunoediting also known as?
immune surveillance
What happens during the elimination phase of cancer immunoediting?
immune system recognises and destroys tumour cells (immune surveillance)
Which cells are involved in the elimination phase of cancer immunoediting?
NK cells, CD8+ T cells, macrophages
When would the elimination phase progress to the equilibrium phase of cancer immunoediting?
if the immune system does not completely eliminate all transformed cells / poorly immunogenic cell escapes destruction
What happens during the equilibrium phase of cancer immunoediting?
there is a balance between immune control and tumour growth (cancer dormancy). tumour cells are contained but not all eliminated.
How may equilibrium represent the end stage of cancer immunoediting?
growth may be restrained for the lifetime of the host
What happens during the escape phase of cancer immunoediting?
tumour cells evade immune detection and control
How may the equilibrium phase of cancer immunoediting progress to the escape phase?
the cancer cells acquire further mutations to evade the immune cells to progress to clinically detectable malignancy
What mechanisms do tumour cells use to escape the immune system?
altered antigen presentation, express inhibitory molecules, produce immunosuppressive factors, resist immune effector mechanisms
How do tumour cells alter their antigen presentation to evade the immune system?
lose MHCI expression, defects in antigen processing (so no antigen is presented)
What are the inhibitory molecules expressed by tumour cells to evade the immune system?
PD-L1 (binds to PD-1 on T cells), CTLA-4 ligands (B7)
What immunosuppressive factors are produced by tumour cells?
TGF-beta, IL-10, prostaglandin E2
What is the function of the immunosuppressive factors produced by tumour cells?
they recruit immunosuppressive cells
Which immune effector mechanism do tumour cells resist?
apoptosis
How do tumour cells resist apoptosis?
express anti-apoptotic molecules
Which cells express PD-L1?
tumour cells or immune cells (to inhibit T cells)
Which cells express PD-1?
T cells
What happens when PD-L1 on tumour/immune cells bind to PD-1 on T cells?
the T cell is deactivated (PD-L1 is an inhibitory molecule)
Which molecules on tumour/immune cells and T cells can interact?
MHC-TCR interact and PD-L1 and PD-1 interact
How are T cells activated by tumour/immune cells?
anti PD-L1 antibodies and anti PD-1 antibodies bind to PD-L1 on tumour/immune cells and to PD-1 on T cells respectively, blocking the receptors. Prevents the interaction between PD-L1 and PD-1 which would deactivate T cells
Examples of checkpoint proteins
B7-1, B7-2 (CTLA-4 ligands) on APCs, CTLA-4 on T cells (keep immune system in check)
Which cells express B7?
Antigen presenting cells
Which cells express CTLA-4?
T cells
How are T cells inactivated via the immune checkpoint pathway?
Via the binding of B7 (on APCs) to CTLA-4 (on T cells) as well as MHCII-TCR interaction
How are T cells activated via the immune checkpoint pathway?
anti-CTLA-4 antibody (immune checkpoint inhibitor) binds and blocks CTLA-4 (from B7 binding)
What are the 7 key stages of the cancer immunity cycle?
- release of cancer cell antigens (cell death)
- Cancer antigen presentation (APCs)
- Priming and activation (T cells) in LNs
- cytotoxic T cells travel to tumour via BVs
- T cells infiltrate tumour
- T cells recognise cancer cells
- cancer cells are killed
What two opposing characteristics of the immune response dictate tumour fate?
effector immune response and tolerogenic immune response
Which type of immune response occurs during tumour initiation?
Tumoricidal effector response (to eliminate immunogenic cancer cells)
Which type of immune response is present during metastatic dissemination?
immune tolerance (tolerogenic)
Which cells are involved in the tumoricidal effector response?
NK cells, CD8+ T cells, Th1 CD4+ T cells, cytotoxic macrophages, neutrophils
Which cells are involved in immune tolerance?
Pro-tumoral macrophages, regulatory T cells, regulatory B cells, immature DCs, pro-metastatic neutrophils
Examples of tumour-infiltrating immune cells (either stimulate/inhibit cancer)
tumour-associated macrophages (TAM), regulatory T cells (Tregs), tumour-infiltrating lymphocytes (TILs)
What type of macrophage are tumour-associated macrophages (TAMs) often polarised to?
M2 (pro-tumour)
How do tumour-associated macrophages promote tumour growth?
promote angiogenesis, invasion, metastasis, and produce immunosuppressive cytokines
How do regulatory T cells (Tregs) promote tumour growth?
suppress effector T cell function (Tregs associated with poor prognosis)
Which cells are tumour-infiltrating lymphocytes (TILs)?
CD8+ cytotoxic T cells
Why is a high CD8+ TIL density associated with better prognosis?
CD8+ cytotoxic T cells eliminate tumour cells
Which cells form the basis for adoptive cell therapy?
CD8+ tumour-infiltrating lymphocytes
Function of M1 macrophages
release cytokines that induce proinflammatory and antitumor immune responses
Function of M2 macrophages
release anti-inflammatory cytokines that suppress the immune response and promote tumour progression
Which cells play a critical role in immunosurveillance?
Natural Killer cells
How do NK cells fulfil their anti-tumoral function?
secrete lytic granules, produce cytokines (both use activating receptors) and express death receptors
Which NK cell receptors lead to cytokine and lytic granule release?
activating receptors
Function of death receptors on NK cells
induce apoptosis
What is the tumour microenvironment?
a complex ecosystem surrounding the tumour that can be immunosuppressive or immunostimulatory
What is a tumour microenvironment made up of?
immune cells (lymphocytes, macrophages, DCs), stromal cells (fibroblasts, endothelium), ECM, soluble mediators (cytokines, chemokines)
What are some common benign oral neoplasms?
papilloma, fibroma, lipoma, pleomorphic adenoma
How are benign oral neoplasms usually treated?
surgical removal
Which virus is associated with the development of a papilloma?
HPV (human papillomavirus)
Description of papilloma
exophytic, cauliflower-like growth
Which is the most common oral benign tumour?
fibroma
Why is fibroma not considered to be a true neoplasms?
It is reactive hyperplasia
Description of a lipoma
soft, yellowish submucosal mass
What is the most common benign salivary gland tumour?
Pleomorphic adenoma
Which salivary glands are typically affected by pleomorphic adenoma?
major salivary glands
What are the common malignant oral neoplasms?
squamous cell carcinoma, verrucous carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma
What percentage of oral malignancies are due to squamous cell carcinoma?
90%
Which areas of the oral cavity are more likely to develop SCC?
lateral tongue, floor of mouth
Which malignancy is verrucous carcinoma a variant of?
SCC
Description of verrucous carcinoma
exophytic, warty appearance
What is the most common malignant salivary gland tumour?
mucoepidermoid carcinoma
What is the route of metastasis for adenoid cystic carcinoma?
perineural invasion
What are the clinical manifestations of oral neoplasms?
erythroplakia/leukoplakia, non-healing ulcers, indurated masses/swellings, pain or paraesthesia, tooth mobility w/o periodontal disease, dysphagia/speech difficulties, lymphadenopathy, weight loss/systemic symptoms in advanced cases
What is a red patch called?
erythroplakia
What is a white patch called?
leukoplakia
