Tumour Immunology Flashcards
Types of TAAs
Mutated self proteins
Aberrantly/overexpressed self proteins
Lineage specific antigens e.g. Mart1/Melan A in melanoma
Abnormal post translational modification of self protein e.g. over/under glycosylation
Viral proteins - foreign
Tumour stroma + microenvironment
What makes a good target for tumour immunotherapy.?
Tumour specific e.g. mutated self proteins
Shared amongst same + diff cancers e.g p53 mutation
Critical for tumour growth + survival
Lack of immunological tolerance so T cells can react
Lineage specific antigens are usually not good
Molecules that aid adhesion of T cell to APC
ICAM (binds to T cell LFA)
ICAM-3 on T CELL
CD2/LFA-3
How can tumours escape immune response?
- loss of MCH i expression
- reduced expression of other molecules involved in antigen processing e.g. TAP1 in colorectal cancer
- loss of costimulatory molecule expression (CD80/86)
- loss of target antigen
- overexpression if enzyme inhibitors to prevent performing-granzyme mediated lysis
- inhibit T cell infiltration
How do tumours inhibit T cell infiltration?
Endothelial B receptor on tumour signals to prevent modulation of ICAM recusing adhesion of T cell to tumour vasculature
Nitrosylation of chemokines keep T cells from entering tumour core
How many immunosuppressive occur at the tumour site?
TGF-b produced by tumour suppresses T cells + induces Treg
IDO expressed by tumours block CD8 cell proliferation + promotes apoptosis of CD4 + induces T Reg
Secretion of local factors that inhibit DCs e.g. VEGF, IL-6, IL-10, TGF-b
Expression of FAS-L by tumour can cause death of CD95 (FAS) expressing Tcells
What are MDSCs?
cells of myeloid origin (progenitor + immature cells)
expand during cancer, inflammation + infection
suppress t cell function by up-regulating factors such as arginine 1, iNOS
- these metabolise L-arginine which is required for T cell function
iNOS generates NO that induces T cell apoptosis & induce Treg
Types of T cell, based therapy for cancer?
Non specific T cell stimulation (checkpoint blockade?)
Vaccination
Adoptive T cell therapy
Types of non specific T cell stimulation
Immunostimulatory cytokines e.g. IL2 - toxic results —> vascular leak syndrome
Immune checkpoint blockade
Types of tumour vaccination
Tumour cells/lines (irradiated)- successful but poor. immunogenicity, lack of costimulation?
Defined tumour specific peptides - purified/expressed from recombinant viruses
DC based - pre load DCs w tumour proteins + insect back into patient
Types of adoptive T cell therapy
Infuse whole T cell population - risk of gvhd
Infuse tumour specific T cells (TIL therapy)
- T cells activated in vitro to be tumour specific to achieve high conc of activated cells in vivo (no gvhd)
- T cells taken form patient the self or donor
Can be combined w vaccination
Genetic engineering of T cells to make in tumour specific
Problem with TIL therapy?
Difficult to select tumour specific lymphocytes (they all look the same)
What are chimeric antigen receptors?
Fusion between TCR and antibody - MHC unrestricted & highly potent
Target any surface molecules not just epitopes (unlike TCR)
Works well for CLL & ALL
Drawback of using chimeric antigen receptors?
Cytokine storm (too much signalling) T cells may target other cells e.g. those expressing HER2
Side effects of immune therapy?
iRAEs related to CTLA-4 blockade
Evidence of tumour enhancement due to increased inflammatory cytokines —> angiogenesis, tissue remodelling, DNA damage etc.
Autoimmunity esp w blockade & TIL therapy
- TIL —> autoimmune melanocyte destruction as it targets antigens all over body, not just tumour (vitiligo, uveitis)
Autoimmunity can be treated w steroids
