Tumour Immunology Flashcards
How do tumours develop?
Single cell develops altered growth properties
The cell proliferates forming a benign tumour
Tumour becomes invasive - now a malignant tumour
Metastasis via local blood vessel or lymph duct
What is some important cancer terminology?
Cancers
= classified according to their embryonic tissue origin
Carcinomas
= tumours that develop from epithelial origins
(skin, gut or epithelial linings)
Sarcomas
= derive from mesodermal connective tissue
(bone, fat and cartilage tissue)
Lymphomas, myelomas, leukemias
= derive from haematopoietic stem cells
= leukemias involve early stage development of bone marrow cells
= lymphomas and myelomas arise from cells after migration out of bone marrow
What is malignant transformation?
Transformation
= process by which a normal cell acquires the properties of a tumour cell
= can be benign or malignant
Initiated by:
= exposure to carcinogens which damage the cell’s DNA
(e.g. UV light, tobacco smoke, asbestos)
= infection with tumour-causing viruses that integrate into cell’s genome
(e.g. HPV - cervical carcinoma, EPV - Burkitt’s lymphoma)
Transformation is a multi-step process
= required several changes in genes that regulate cell proliferation + apoptosis
Some people have genetic pre-disposition
= cells more likely to become transformed
= e.g. BRCA1 - breast cancer
What are the genetic changes in cancer?
Cancer-associated genes that change during transformation:
Proto-oncogenes
= genes that promote normal cell proliferation
= turned into oncogenes which promote uncontrolled growth when mutated or overexpressed
= e.g. K-Ras, Src, Myc
Tumour suppressor genes
= inhibit cell proliferation and can be mutated or lost during transformation
= e.g p53, BRCA1/2, APC, Rb
Apoptosis regulators
= sequences that control programmed cell death
= e.g. Bcl2
= can be inactivated or altered
Tumour-causing viruses express cancer causing factors:
Viral oncogenes
= often similar to cellular oncogenes and drive cell growth
= e.g. vSrc in Rouse sarcoma virus, acquired from out genome
Viral inhibitors of tumour suppressor genes
= e.g. E6 protein from HPV inhibits p53, PHV E7 inhibits Rb
What are some genetic changes in Colon Cancer?
APC, DCC, TP53
= tumour suppressor genes
= these are lost
K-Ras
= an oncogene linked to proliferation
= this becomes activated
How can tumours be detected by the immune system?
Tumours derived by own cells
= BUT they can express some antigens that can be detected as “non-self” or “altered self” by immune self
Tumour antigens can be:
TSA - Tumour Specific Antigens
= unique to the tumour
= e.g. mutated oncogenes or viral proteins - HPV E6/E7 in cervical carcinoma
TAA - Tumour-Associated Antigens
= normal proteins that are over-expressed in cancer
= e.g. overexpressed oncogenes - HER2 - breast cancer
e.g. re-expressed embryonic genes on cofoetal antigens - AFP in liver cancer
= antigens presented on MHC I molecules on surface of tumour cells
= replication stress and DNA damage may also cause expression of ligands for NK cell activation
= DCs and macrophages can present tumour-derived antigens to T and B cells
= they secrete cytokines (E.g. TNF-α, Interferons) which promote Th1 immune response
= if detected, tumour cells can be killed by NK cells, inflammatory macrophages and CTLs
How does the immune system constantly protect us from cancer?
Cancer immunosurveillance
= detection and elimination of transformed cells or tumour cells by immune system
= immunosuppressed individuals / immunodeficiency patients more susceptible to certain cancer types
What is immuno-editing?
(immune system can protect from some cancer BUT can also promote tumour growth)
Immunoediting is the process by which immune system shaped tumour development by:
= eliminating some tumour cells (immunosurveillance)
= causing selection of tumour cells that escape immune recognition
= creating an inflammatory microenvironment that can promote tumour growth
Has 3 sequential phases:
Elimination
= tumour cells killed by immune system
Equilibrium
= the immune system restricts tumour growth
Escape
= selection pressure causes the outgrowth of tumour cells that are no longer sensitive to immune attack
How can tumour cells evade detection by the immune system?
Not all cancer cells are detectable
= e.g. if they don’t express any appropriate antigens
Tumour cells also often LACK co-stimulatory molecules
= CD80/86 = required for activation of T cells
As tumour cells are genetically unstable
= they can evolve to escape selection pressure from immunosurveillance
Tumour cells can evade immune rejection by establishing an immunosuppressive microenvironment by:
= downregulating the expression of MHC, tumour antigens or ligands for NK cells
= secreting immunoregulatory cytokines
(e.g. TGFβ which inhibits NK cell + cytotoxic T cell activity)
What is an example of Immune avoidance / evasion?
= escape mutants
= immunosurveillance results in the killing of tumour cells that express class I MHC and tumour antigens
= the selection pressure of immunosurveillance means that the few tumour cells with low MHC expression survive
= cells with low MHC expression can proliferate and are no longer detected by immune system, they are escape mutants
What are some cancer treatments?
= Surgery - remove discrete tumours
= Radiotherapy - destroy discrete tumours
= Chemotherapy - selectively block tumour cell growth
= Hormone therapy - to interfere with tumour cell growth
= Targeted therapy with small molecule inhibitors of signalling pathways important in cancer development
= Immunotherapy - reviving, initiating or supplementing the anti-tumour immune response
What is Immunotherapy?
= therapies that aim to invoke an immune response to the tumour cells
= increasingly being developed along or in combination with other therapy approaches
= goal is to promote a strong tumour-specific cytotoxic T cell response
= can also use properties of antibodies to target drugs, toxins and radioisotypes specifically to cancer cells
What are monoclonal antibodies?
= generated in mouse hybridoma cell lines grown in culture
= a particular hybridoma cell line generates antibodies that all have the same specificity
= have developed: monoclonal antibodies that recognise tumour-specific or tumour-associated antigens or surface proteins
= that regulate the immune response
Humanised antibodies
= genetically engineered to be more similar to our own antibodies
= therefore activate the human immune system more effectively
= are not eliminated as quickly
Several monoclonal antibodies licenced for cancer treatment
e.g. Trastuzumab (Herceptin)
= against Her2-expressing breast cancer
e.g. Rituximab (Rituxan)
= against the B cell marker CD20 for Non-Hodgkin’s lymphoma
How are monoclonal antibodies used against tumour antigens?
Monoclonal antibodies specific to a tumour antigen
= can be used to alert complement, NK cells and macrophages to the tumour
ADCs - Antibody Drug Conjugates
= tumour-specific monoclonal antibodies coupled to toxins, drug molecules or radioisotypes to directly kill tumour cells
How do monoclonal antibodies work against surface receptors?
Monoclonal antibodies also used to block interaction between surface receptors and their ligands
Used to
= block growth receptors on tumour cells
(e.g. Herceptin blocks HER2 receptor)
= block vascular endothelial growth factor (VEGF) signalling
= therefore inhibits growth of blood vessels around the tumour
(e.g. Bevacizumab - Avastin)
How do monoclonal antibodies work on immune checkpoint inhibitors?
Monoclonal antibodies used to block binding of co-inhibitory receptors on T cells
(received 2018 Nobel Prize)
= block binding of CD80/86 using mAb against CTLA-4
= block binding of PD-1 to PD-L1 using mAb against either PD-L1 (atezolizumab) or PD-1 (nivolumab and pembrolizumab)
= releases T-cell inhibition enabling anti-cancer response
What is CAR T-cell therapy?
= Chimeric Antigen Receptor T cell therapy
= adoptive T-cell transfer of in vitro modified autologous T cells from patients with cancer
- Isolate patients peripheral T cells
- Insert the gene for a chimeric antigen receptor (CAR)
- The CAR is specific for a defined tumour antigen
- Re-infuse tumour specific CAR T-Cells into patient
CARs are:
= externally like a BCR (no requirement for MHC restriction)
= internally signals like a TCR including a domain for co-stimulation
What are the disadvantages of CAR T-cell thearpy?
Cytokine Release Syndrome
= systematic activation of highly proliferative cytokine secreting CAR T-cells
= resulted in high fever, flu like symptoms with neurological impact, resulted in some deaths
= changed delivery protocol to provide anti-IL-6 monoclonal antibodies
= to ‘mop up’ the excess inflammatory cytokine
= enabled trials to continue
First approved by FDA in 2017
(Tisangenlecleucel-T)
= Acute lymphoblastic leukaemia patients aged 3-25
= 83% patients in complete remission within 3 months
= no deaths due to treatment
Multiple new CAR designs in progress
What are some Cancer Vaccines?
Phophylatic vaccines
= aim to prevent disease
= only one vaccine available - HPV
Therapeutic vaccines
= treat cancer by enhancing appropriate immune responses to kill tumour cells
= can be virus based or cell based
Virus-based
= engineered to express cancer antigens and co-stimulatory molecules
= e.g. ProstVac VF based on vaccinia virus expressing prostate specific antigen + co-stimulatory molecules (LFA3, ICAM1 and CD80)
= virus gets taken up by APCs
= induces cytotoxic T cell response against tumour cells expressing PSA
= early success in trials , but no effect on survival in phase 3 for metastatic prostate cancer
Cell-based
= immune cells (e.g. DCs) isolated from patient, stimulated to respond to the tumour and injected back into body
= e.g. Sipuleucel-T for prostate cancer
= immature monocytes isolated from patient
= cultured with cytokine GM-CSF fused to antigen PAP
= GM-CSF induces maturation of DCs and PAP is presented to MHC
= cells injected back into patient
= cytotoxic T cell response induced to the PAP antigen on tumours
= has small effect on survival
How do immunotherapies make conventional therapies more effective?
= Chemo / Radio therapy causes DNA damage and tumour cell death
= Dendritic cells take up dead tumour cells and present tumour antigens to cytotoxic T cells
= Tumour specific cytotoxic T cells can also eliminate metastases that were not originally targeted by the treatment
