TUMOUR IMMUNOLOGY

What did Rudolf Virchow note in 1863

that leukocytes in tumours proposed a link between chronic inflammation and cancer origin

What did William Coley note in 1891

observed spontaneous tumour regression after severe bacterial infection

What did Paul Elrich propose in 1909

proposed that the immune system might naturally suppresss the outgrowth of neoplastic cells arising in the body

What is the core claim of the immunoserveillance hypothesis

a physiological function of the immune system is to continuously recognise and destroy clones of transformed cells before they become tumurs, and to kill tumours after they’ve formed

explain the initial result and the revival results of Osias Stutman’s experiments

initially in athymic mice, there was little to no increase in tumour incidience

then in the revival, truly immunodeficient mice did develop significantly more spontaneous and carcingoen induced tumours than noraml mice

What are the 3 E’s of cancer immunoediting

Elimination

Equilibirum

Escape

explain ‘Elimination’

innate and adaptive immunity detect and destroy transformed cells

explain ‘Equilibrium’

surviving tumour variants are contained, not destroyed

a dynamic stand off

define ‘Escape’

select variants evade immune control

clinically detectable cancer emerges

what did James Allison show in 1996

that blocking CTLA-4 (T cell brake) could cure established tumours in mice

what did Tasuku Honjo show in 1992

Identified PD-1, its role as a tumour exploited checkpoint was established over the following decade

what are the core functions of the immune system relative to cancer

removal of diseased/transformed cells

precise targeted killing

woud healing

long term immunological memory

what disease categories does the immune system govern

cancer

infectious disease

autoimmune disease

cardiovascular disease

neurodegenerative disease

inflammatory disease

what is evidence of tumours eliciting an immuen response

histopathology shows many tumours surrounded by mononuclear infilatrates such as T cells and NK cells

what is an immunoscore

the quantification of CD3+/CD8+ T cell density in tumour core and invasive margin, producing a score from IS0 to IS4 (low to high)

describe the relationship between immunoscore and relapse risk & survival rate

increase immunoscore = decreased relapse risk and better survival rate

do tumours express antigens

yes they do

what can reactivate the immune system

external stimuli

How do cytotoxic T cells act against tumours

the principal mechanism is direct killing

T cells recognise the peptides derived from tumour antigens presented on the MHC Class I

Why are tumour cells perfect targets for NK cells

because some tumours express ligands for the activating receptor

how can NK cells be directed to tumours

they can be directed to IgG coated tumour cells by Fc receptors

How do macrophages act against tumours

M1 type → kill tumour cells directly by nitric oxide production

M2 type → promote tumour growth and invasion

what do neoantigens arise from

tumour specific mutations that generate novel peptide sequences

why are neoantigens ideal immunotherapy and vaccine targets

because they afre not in normal tissue, so they avoid central and peripheral self tolerance mechanisms

which tumours accumulate far more somatic mutations

tumours which have DNA repair machinery defects

what are the 2 broad categories of antigens recognised by endogenous T cells

tumour associated antigen → shared, lower specificty

tumour specific antigens → neoantigens, highly specific

what does epitope detection depend on

the hosts HLA type and how efficiently the epitope is processed and presented

what does MDSC stand for

myeloid derived suppressor cells

describe MDSCs

immature myeloid cell that expands dramatically in cancer

what is the roles of MDSCs

they suppress the adaptive immunity ; inhibiting CD4+,CD8+ T cell activation/function

they suppress innate immunity; polarising macrophages toward the tumour to promote M2 phenotype and inhibit NK cell cytotoxicity

what are the 3 passive evasion mechanisms

specialised evasion machinery

weak immunogenicity

kinetic escape

explain specialised evasion machinery

many tumours actively downregulate antigen presentation or immunogenic signalling

explain weak immunogenicity

as tumour cells are derived from host cells, most spontaneous tumours resemble normal tissue and so they are only weakly immunogenic

explain kinetic escape

rapid tumour growth and spread can simply outpace the immune systems capacity to eliminate every malignant cell

what does TGF-Beta do

inhibits the proliferation and effector function of lymphocytes and macrophages

secreted by tumour cells

what are M2 macrophages

tumour associated macrophages which promote invasiveness and remodel the microenvironemnt via secretions that impair T cells and promote angiogenesis

what are the 4 categories of evasion

reduced visibility

active suppression

physical/metabolic

kinetic escape

what is invovled in reduced visibility evasion

low antigenicity

MHC-1 downregulation

antigen loss variants

what is invoved in active suppression evasion

CTLA-4/PD-1

TGF-beta, IL-10

Tregs, MDSCs, M2 TAMs

what is involved in physical/metabolic evasion

hypoxia, nutrient depletion

stromal/matrix barriers

heterogenous TME

what is involved in kinetic escape evasion

rapid prolfieration

outpacing elimination

immunoediting towards escape variants

what are some immunotherapy strategies

checkpoint blockade

adoptive cell therapy

engineered receptors

cancer vaccines

explain immune checkpoint blockade

tumour patients upregulate inhibitory receptors, like PD-1, on tumour specific T cells

PD-1 tells T cells to stop attacking cancer

by blocking anti-PD-1 antibodies has shown efficacy across cancer types as this releases the brakes on T cells

explain adoptive cell therapy

lymphocytes from the patient are extracted, and expanded ex-vivo in IL-2 then infused back into the patient

helps lead to tumour regression

what does CAR stand for

chimeric antigen receptors

explain engineered receptors

uses CAR-T cells and related cell engineering approaches to redirect T cells to tumour antigens independent of MHC

explain CAR-T cells workflow

T cells are collected from a patient

T cells are transduced with CAR gene

T cells then expanded

T cells infused back after lymphoma depleting conditioning

how do cancer vaccines aim to work

they aim to prime new tumour specific T cell responses directly

briefly explain cancer vaccine production

tumour is sequenced to identify patient specific mutations

neoantigens predicted by ranking mutations most likely to be presented and recognised

vaccine designed and manufactued, packaging in a lipid nanoparticle

vaccine then delivered to patient, usually combined with a checkpoint inhibitor and/or chemotherapy