Unit 4: tumor Flashcards
evidence that tumors are immunogenic
Immune compromised animals have an increased incidence of tumor
development (epithelial tumors, lymphomas, leukemias etc)
Tumor antigen-specific T cells present in tumor bearing hosts
Spontaneous regression of established tumors
Response of some tumors to non-specific immune activation (e.g. post surgical infections in OSA; Coley’s toxins)
Presence of tumor antigen escape variants suggest immunological pressure
Cytotoxic T cell infiltrates confer ___ prognosis
favorable
Regulatory T cell infiltrates confer ___ prognosis
poor
Tumor Immunogenicity depends on tumor __
mutational load
as tumors grow- they will change and develop mutations that can be attacked by the body
tumors caused by carcinogens have more mutations and more reactions to T cells
anti PD-1 therapy
give drug that prevents T cells from being turned off → leading to immune response that shrinks the tumor
Blockade of inhibitory T cell signals leads to dramatic therapeutic responses in human patients with refractory melanoma
___ collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas
Lymphocytes and IFN-γ
Immune attack leads to the selection of tumor cells that are ___, which explains the apparent paradox of tumor formation in immunologically intact individuals.
more capable of surviving in an immunocompetent host
body kills weak tumor cells, strong survive to live and spread
Concept of Immune Surveillance & Immune editing
The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective ___
T cell responses
Addressing the immune suppressive Tumor Microenvironment is essential for effective ___
anti-tumor immunity
Why does anti-tumor immunity fail?
• Lack of ___(down regulation of MHCI)
- Changes in TAA and antigen-presentation capacity – mutations or silencing of genes involved in ___
- Tumor antigen ___ (mucopolysaccharides, fibrin)
TCR recognition
IFN-γ response
masking
Why does anti-tumor immunity fail?
Lack of sufficient T cell activation, failure of __ of antigen-specific T cells
- ___ of immune activation by tumor
- Suppression of activation by ___ in TME
clonal expansion
Suppression
inhibitory cells/mediators
Why does anti-tumor immunity fail?
T cell exclusion from TME
• Changes in tumor susceptibility to the cytotoxic response – less susceptible to apoptotic and necrotic effects (up-regulation of anti-apoptotic proteins or loss of death receptors, eg. ___)
TRAIL receptors or FAS
The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective T cell responses
Regulatory Immune Cells
Immune Suppressive cytokines and enzymes
Checkpoint molecules
Tumor Stroma
(Tregs, Myeloid Derived Suppressor Cells (MDSC), TAM
Regulatory Immune Cells
The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective T cell responses
(IL-10, TGF-B, IL-35, IDO, arginase etc.)
Immune Suppressive cytokines and enzymes
The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective T cell responses
(CTLA-4, PD-1, PD-L1)
Checkpoint molecules (CTLA-4, PD-1, PD-L1)
The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective T cell responses
two ways regulatory T cells can suppress
dominant consumption of IL2- reg 2 produce a lot of CD25 which use up IL2
Inhibitory cytokines- Treg produce inhibitory cytokines TGFB, IL10 and IL35 that will prevent effector T cells from acting normal
induction of apoptosis- Treg have lots of FAS that will bind to and kill T cells
two major type of MDSC
Monocytic (M-MDSC) and PMN (PMN-MDSC)
PMN-MDSC –
share phenotypic and morphological features with neutrophils
M-MDSC -
similar to monocytes; can differentiate to immunosuppressive
macrophages (TAMs/ M2) and tolerogenic dendritic cells in the TME
MDSCs do not differentiate into immunogenic ___
DCs or inflammatory macrophages
In solid cancers, (melanoma, renal, lung, prostate) – increased ___ in circulation – correlates with tumor stage, volume and prognosis.
MDSC
of circulating __is a prognostic factor in DLBCL (especially PMN-MDSC)
MDSCs
MDSC have Direct suppressive effect on___responses
NK and CTL
MDSC have NOS and ROS nitration of the TCR on CTLs preventing ___ interaction
MHC
In MDSC, Arginase depletes extracellular arginine, preventing___cell activation
CD8 and CD4 T
Arginase helps expand ___ population
Treg
M2 monocytes
tissue repair and angiogenesis
tumor promotion
down regulation of M1 and adaptive immunity
TAM are type ___ and are involved in___
M2 monocytes
metastasis, down regulation of adaptive immunity and tumor production
IL 10 is made by __ and does what
IDO is made by ___ and does ___
immune checkpoints
down regulate immune response after elimination of disease
Prevent too strong an immune response that may damage normal tissues
Maintain immune tolerance/peripheral tolerance to self antigens
Many have been identified, but CTLA-4 and PD-1 are the two that have been best characterized
Mouse models in which either CTLA-4 or PD-1 has been deleted results in systemic autoimmunity
CTLA-4
checkpoint
that stops cell from starting
CTLA found on T cell, will interact with CD80/86 and will inhibit/turn off the T cell
CTLA found on Treg will cause activate in function of Treg
PD-1
checkpoint
that stoped “car” as it is driving down the road
when T cell activated, PD-1 upregulated, will bind to PD ligand and will turn off T cell
CTLA-4 has higher affinity for ___ interrupting activation signal, downregulating T cell function and inhibiting excessive T cell expansion
CD80/86,
In the TME, tumor-specific T cells are inactivated by ___ on
the tumor cell resulting in tolerance/anergy
PD-L1 or PD-L2
Cancer cells exist in a ___relationship with their local microenvironment
symbiotic
The ___ is complex, and like tumor cells, evolves in response to environmental pressures
microenvironment
Standard therapies do not address the___ and its contribution to oncogenesis/tumor cell survival
local immunosuppression
Failure of anti-cancer therapies to eradicate tumor cells, especially in the setting of metastatic disease, is likely in part due to the presence of ___ in the tumor microenvironment
immunosuppression
Improved efficacy of immunotherapy will likely require combination therapies to address the __
TME
The goal of cancer immunotherapy is to initiate / augment a self-propagating cycle of anti-tumor immunity that further ___ responses
amplifies and broadens tumor-specific T cell
steps of cancer immunity cycle
tumor associated antigens
found on tumor cells and normal cells
Qualitative and quantitative differences distinguish normal from abnormal
how do autologous and allogenic whole tumor cell vaccines work
take out tumor
change it, put part of it back in, will either start Tcell response
or will be eaten by APC and antigen is presented and starts a T cell response
polycolonal CD4 and CD8 response
These tumor specific t cells, taken out, multiply in lab and then giving back to body
peptide vaccine
supply short amino acid sequence, which sits in MHC groove on ATC
only work for specific MHC haplotypes
not as popular in vet cause MHC not well understood
oncept
DNA vaccine for melanoma with human tyrosinase in it
DNA vaccine
have plasmid (circle of DNA) codes for tumor antigen
eaten by APC and presented to cause Tumor specific T cell reaction
explain
remove tumor
sequence and look for mutations that result in new protein
take all the changes, and link together
and give back to body as DNA vaccination against it
two things that can be used as biological vector to deliver tumor associated antigen
Adenoviral vectors
Listeria monocytogenes based vaccines
adenoviral vector
used to deliver TAA(tumor associated antigens) DNA into cell
generates cytotoxic T cell responses against TAA
eg. Telomerase
listeria monocytogenes based vaccines
change bacteria so that it is not harmful and so it expresses the tumor associated antigen of interest
delivers TAA into MHC 1 and II processing pathway
generates potent CD4 and CD8 T cell responses against TAA
MHC 1→ CD8
MHC 2→ CD4
MHC 1→ __
MHC 2→ ___
MHC 1→ CD8
MHC 2→ CD4
canine OSA vaccine
listeria monocytogenes expressing HER2
will be eaten by cell and cause CD4 and CD8 T cell immunity
vaccine helped reduce formation of tumor(OSA)
APC based cancer vaccine
isolate monocytes → change to immature DC cells in lab → then give them specific antigenic payload
activated antigen specific DC are put back into body to cause immune response
sipulenucel (for prostate cancer)
adoptive T cell therapy
ACT
bypassing the need for vaccine- trying to generate activated T cells outside body and then put back into body
Large numbers of autologous anti-tumor lymphocytes are generated ex vivo
• Uses T cells that recognize tumor antigens (e.g. Tumor Infiltrating
Lymphocytes (TILs)) or genetically engineered T cells
• Pre-conditioning regimes “prepare” the patient for adoptive transfer
• “Living therapy” – administered cells survive, proliferate and kill tumor
cells
ACT use T cells that recognize tumor antigens (____) or ___
tumor infiltrating lymphocytes (TILs)
genetically engineered T cells
take T cells out, mature them then put them back, will kill cells and multiply (living therapy)
ATC using TILS
take out tumor
isolate T cells inside that are specific for tumor, grow them then put them back in
Non-myeloablative therapy (or TBI) prior to adoptive transfer improves the degree and duration of the response
<80% of circulating CD8+ T cells are specific for tumor in some cases
TIL success is mostly limited to malignant melanoma patients (+/- lung and bladder) –tumors with high mutational load
CARs
ACT with genetically engineered T cells
take out T cells, change them by adding chimeric antigen receptors and tumor specific TCR (adds antibody vs normal T cell receptor)
then putting them back into person
why use antibody on T cell rather then normal receptor
cancer cells will change their MHC complexes, normal T cells can’t see
antibody will be able to see mutated cancer cell
don’t need MHC or costimulatory molecule on cancer cells
Defects in APC function in cancer
Mutations in MHC I and down regulation of TAP and ERp57 reduce
surface expression of peptide loaded MHC-I
Tumor derived IL-6, IL-10 and VEGF inhibit IL-12 production and
decrease expression of MHCII-peptide, co-stimulatory molecules and
LN homing molecules on APCs
IL-6 and IL-10 suppress DC maturation and promote DC dysfunction
Tumors promote production of TGF-β, IDO and galectin-1 by DCs
which promotes a tolerogenic phenotype and Treg generation
Malignant B cells have defects in MHCII expression
problems with CAR T cell
SEVERE ON-TARGET, OFF-TUMOR SIDE EFFECTS
ELIMINATION OF “NORMAL” CELLS EXPRESSING TARGETED ANTIGEN
CYTOKINE STORMS AND MACROPHAGE ACTIVATION SYNDROME
3 ways monoclonal antibody therapy can work
PDL1
T cell will attack tumor, tumor will produce PDL1 which will turn off T cell
we can use anti PD1, anti PDL1 and anti CTLA4 to turn off tumor stop signal and allow Tumor specific T cells to work again
what therapies work at the 7 stages of tumor cycle
immune suppressive networks in the TME
