cancer immunotherapy

tumour immunosurveillance hypothesis

T cells detect tumour antigens
neoantigens pre existing or as a consequence of GIN
viral proteins detected
tissue self antigens - loss of self tolerance
NK cells recognise cold tumours

evidence against tumour immunosurveillance

cancers grow in immunocompetent hosts
cancers derive from tolerised self tissues
nude mice are not more susceptible to tumours

evidence for tumour immunosurveillance hypothesis

TILs correlate with prognosis
neoantigens recognised by T cells
Rag and IFNg deficient mice are more susceptible to carcinogen induced tumours

evidence for cancer immunoediting

wt or rag2 KO mice injected with carcinogen and tumours transfered into rag2 KO or wt mice
WT tumour grew in rag2KO mice and wt mice
rag2 KO tumour only grew in rag KO mice - tumour adapted and evolved to absence of immune system so is rejected by wt immune system

cancer immunoediting hypothesis

normal tissue transforms
elimination by immune system
equilibrium - dormancy and editing
tumour cell escape

tumour immunity cycle

migratory DCs take up tumour antigen and go to LN
presents to T cells which activate and expand
T cells migrate to tumour and kill tumour cells

mechanisms of immune escape by tumours

reduced antigenicity
recruitment of immunosuppressive cells
upregulation of immunosuppressive cytokines and ligands
peripheral tolerance

C9ORF50

identified as tumour intrinsic immune evasion regulator via CRISPR
IDRs drive liquid phase separation in the nucleus facilitating spliceosome organisation
inhibition induces intron retention = creates immunogenic dsRNAs that activate T1IFN responses
KO in mice - more T and B cell infiltration in tumour

strategies used by immunotherapy

activating innate
activating adaptive
reversing immunosuppression

immunotherapy - activating innate immunity

coley’s toxins
BCG
oncolytic viruses
adoptive NK cell therapy

coley’s toxins

historically heat killed streptococcal organisms used against bone sarcomas

BCG

MTb vaccine injected into bladder used for bladder cancer
Th1 memory generated - efficacy in cancer
induces trained immunity in innate cells

oncolytic viruses

directly lyse tumour cells leading to release of soluble antigens
DNA viruses can be encoded with transgenes to increase therapeutic activity
attracts NK and T cells

oncolytic viruses selectively replicate in tumours

capsid can be altered to enhance bidning to tumour cells
Ad3>Ad5 enhances adenovirus binding to tumour cells in melanoma and OC
large pools of nts
dysfunctional antiviral responses in tumour cells

oncolytic viruses antitumour mechanisms

oncolysis attracts NK and T cells
DAMPs and PAMPs activate DCs
TCR mediated killing
upregulation of immune checkpoint molecules by the virus - ICB use

adoptive NK cell therapy

source NK cells from peripheral blood, umbilical chord or NK cell lines and culture

immunotherapy that activates adaptive immunity

adoptive CD8 T cell therapy - TILs, CAR T cells, TCR transduced cells
cancer vaccines
cytokine therapy
agonist therapy

TIL therapy

isolate TILs from patient and culture with IL2
precondition with chemotherapy then reinfuse TILs

CAR T cell therapy

genetically engineered T cells
no HLA requirement
cell surface structures only
hard to extend to solid tumours

TCR transduced T cell

recognition of intracellular and cell surface structures
HLA requirement

cancer vaccines

TSAs are encoded by the vaccine
adjuvants used to boost immunogenicity
LNPs needed for delivery

challenges in cancer vaccines

low immunogenicity
immune evasion
degradation
poor delivery
heterogenous responses

overcoming challenges of cancer vaccines

adjuvants
combination therapy with ICBs
modify peptides
optimise LNP
personalisation

cancer vaccines - LNPs

novel polymeric nanovaccine inspired by octopus tentacle adhesion mechanism
antigens loaded by electrostatic interactions with cationic PEI backbone and coordinate Mn
enhanced DC uptake
Mn activates STING

immunotherapy - reversing immunosuppression

ICBs
Treg depletion

anti PD-1

normally PD1 on T cells signals PPases SHP1/2 to inhibit PKC, Akt and PLCg pathways
inhibits NFAT, NF-kB, mTOR and AP1/2 transcription
nivolumab = anti PD-1

anti CTLA-4

switches off T cell signalling
decreases CD28 binding and T cell activation

ICBs adverse effects

destabilises immunoregulation of autoimmunity
skin related
90% of CTLA4 patients

impact of COVID vaccine on ICBs

prime anti cancer immunity in type 1 IFN dependent manner
mice treated with RNA-LNP and ICB showed reduced tumour size which was reverted with IFNAR blockade

Treg depletion

anti CCR4
anti CD25

barriers to immunotherapy

mutation load
cytokine signalling defects
TME
Treg ratio
metabolic challenge

mutation load

best responding cancers have high mutation frequency
dMMR CRC e.g.

defects in cytokine signalling

acquired resistance to PD-1 blockade in melanoma associated with IFNg defects
KO of IFNgR in solid tumours = reduced control of pancreatic cancer but not haematological cancers
type 1 cytokines drive senescence - p16 and STAT1 dependent

TME

T cell infiltration
cell types

Treg ratio

tumour Tregs have high CCR8 and deletion which leads to immune rejection

metabolic challenge

warburg effect may help sequester glucose from T cells
lactate inhibits T cells
tryptophan converted to kyneurine by IDO which drives T cell suppression