tumour immunology and immunotherapy of cancer Flashcards
role of the immune system: summarise evidence for the importance of tumour surveillance by the immune system, and explain how immune responses to tumours have some similarities with those to virus infected cells
what does PCD patient serum react with
CDR2 protein in tumour tissue (gives strong brown colour, showing antibody binding to tumour), so anti-CRD2 antibody present in serum
significance of neurological symptoms in cancers
antibodies vs tumour have gone to brain and caused neurological disease in brain (autoimmune disease)
what causes autoimmune diseases
spontaneous immune response against tumour-expressed antigen
tumour immunity
immune response against tumour outside of blood-brain barrier
autoimmune neurologic disease
immune response against CDR2 in neurones inside blood-brain barrier
what causes PCD
elimination of Purkinje cells by tumour-induced auto-immune response (immune response against tumour antigen results in destruction of Purkinje cells in brain which normally express CDR2)
what are Purkinje cells
type of motor neurone in cerebellum
what can certain tumour express
antigens that are absent from corresponding normal tissues
what does the immune system upon detection of abnormally expressed antigens by tumours, and consequence
launch immune attack against tumour, which could result in auto-immune destruction of normal somatic tissues
2 direct evidences for immune control over tumours (immunosurveilance)
autopsies of accident victims show microscopic colonies of cancer cells with no symptoms of disease; organs donated by patients who have a history of cancer (melanoma) but were free of disease caused cancer in recipient (donors had “immunity” but recipients didn’t)
2 indirect evidences for immune control over tumours (immunosurveilance)
deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy; men have 2x greater chance of dying from malignant cancer than women (women typically mount stronger immune responses)
describe immunosurveillance
malignant cells are generally controlled by action of immune system
function of immunotherapy
attempt to enhance immune responses to cancer
T cell receptor, and effects on molecules
aB, is “MHC restricted”
B cell receptor, and effects on molecules
antibody, has effect on vast range of molecules (e.g. virus neutralisation)
describe cancer-immunity cycle
release of cancer cell antigens (cell death) -> cancer antigen presentation (dendritic cells/APCs) -> priming and activation (APCs and T cells) -> trafficking of T cells to tumours (cytotoxic T cells) -> infiltration of T cells into tumours (tumour-infiltrating lymphocytes, cytotoxic T cells, endothelial cells) -> recognition of cancer cells by T cells (cytotoxic T cells, cancer cells) -> killing of cancer cells
significance of immune selection pressure (disadvantage of immunotherapy)
any mutations or down-regulations can lead to advantages e.g. tumours lose ability to present MHC, so T cells can’t recognise so huge selection advantage, leading to outgrowth of cells that have down-regulated or have mutations in proteins required for antigen presentation)
what can be targeted in cancer-immunity cycle in “immune checkpoint blockade”, and stages
programmed death ligands (PD-L”x”), in priming and activation and killing of cancer cells (remove negative regulators has same effect as increasing response)
what does initiation of cancer (induction of mutations in cellular DNA) usually result from, and examples
multiple sporadic events over time e.g. irritation, chemical mutagens, spontaneous errors during DNA replication, tumour virus-induced changes in genome
what causes tumour growth
aberrant regulation of apoptosis and cell cycle
what does tumour growth eventually result in, and what does this cause
enough damage to release inflammatory signals, causing recruitment of innate immunity
3 types of innate immunity cells which are initally recruited by inflammatory signals released by tumour growth
dendritic cell, macrophage, natural killer cell
where do innate cells go to
drain into lymph node lymph node to activate adaptive immunity
what happens after recruitment of innate immunity, and what cells does this involve
adaptive, antigen specific immunity (B and T cells), due to presentation of tumour antigens by dendritic cells and APCs
2 requirements for activation of an adaptive anti-tumour immune response
local inflammation in tumour (danger signal) - innate, expression and recognition of tumour antigens - adaptive
2 problems in immune surveillance of cancer
takes tumour a while to cause local inflammation, antigenic differences between normal and tumour cells can be very subtle (e.g. small number of point mutations)
purpose of cancer immunotherapies
teach adaptive immune system to selectively detect and destroy tumour cells
2 uses of cancer immunotherapies
alternative or supplement to conventional therapies (surgery, radiotherapy, chemotherapy)
how do T cells recognise tumour-specific antigens
bind to MHC class I/II molecules, which display contents of cell for surveillance (infection, carcinogenesis); antibodies can also bind directly to surface for recognition
what are tumour-specific antigens
antigens only found in tumour
2 examples of viruses which display viral proteins that are tumour-specific antigens
Epstein Barr virus (EBV), human papillomavirus (HPV)
2 examples of mutated normal cellular proteins displaying tumour-specific antigens
TGF-B receptor III (amino acid change due to mutation), Bcr-Abl (fusion of chromosomes generates new sequence of genes not found anywhere else)
what are opportunistic malignancies
cancers of viral origin which occur when immunosuppressed
2 examples of opportunistic malignancies, and cause of immunosuppression
EBV-positive lymphoma (post-transplant immunosuppression), HHV8-positive Kaposi sarcoma (HIV)
3 examples of cancers of viral origin which exist in immunocompetent individuals
HTLV1-associated leukaemia/lymphoma, hepB virus- and hepC virus-associated hepatocellular carcinoma, human papilloma virus-positive genital tumours
what induces and maintains cervical cancer due to HPV
IC antigens E6 and E7 oncoproteins of HPV
what antigens are targeted for HPV vaccination
uses late gene surface proteins to make virus-like particles (for vaccine)
consequence of cervical HPV infection and HPV-specific T cell immunity if strong immunity due to preventive (prophylactic) HPV vaccination (>99%)
clearance HPV-infection due to immunological memory
consequence of cervical HPV infection and HPV-specific T cell immunity if immune failure as HPV vaccination has been unsuccessful (minority)
cervical neoplasia (50% no immunity, 50% non-functional immunity)
if show early signs of disease, how can HPV vaccine be given
therapeutically
