Inflammation and Immunity in Cancer

recognise self from non-self

The fundamental function of the immune system is to…

bone marrow stem cells, innate cells, adaptive cells, T and B cells

All immune cells arise from _______. There are two main lineages: ______ and _____ (i.e. _______).

pre-armed effectors, not antigen specific, recognises many targets, no antigen memory, inflammation

Innate immunity is rapid because of _______ which are _______ (thus each cell _______). Innate immunity has ______ and drives ______.

phagocytes, dendritic cells, NK cells, and complement

Innate immune effectors include…

conserved microbial structures, e.g. CpG DNA, flagellin, etc.

Innate cells are preprogrammed to recognise…

degranulation or phagocytosis

Mechanisms of innate immune killing:

release of cytotoxic molecules, degranulation, target lysis, vesicles of cytotoxic molecules and ROS, release chromatin fibre NETs that trap pathogens

Activation of granulocytes leads to _______ (“_______”). This causes ______. These cells either contain ______ or they can _______.

engulf target into an intracellular vesicle, ROS and proteases, target destruction

Phagocytes are cells that __________. This contains _______, which leads to ______ and the debris is released.

effectors require activation and proliferation, antigen specific, antigen memory, proteins (antibodies), cells

Adaptive immunity is slow because ______. The response is ______ and creates _______. There are two effector types: _____ and _____.

only one very specific structure

Adaptive immune cells each recognise ________.

Antigen

Molecule recognised by the immune system

Epitope

Specific structure or sequence on an antigen where adaptive immune receptors bind

many epitopes, bound by many immune cells, one epitope

One antigen can have ______, therefore it can be ______. Each immune cells only binds ______ on the antigen.

constant region and variable region

Each immature T or B cell recognises one specific antigen via a specialised receptor that has a…

Constant Region

The same in all T and B cells and determines the receptors function

Variable Region

Different in all T and B cells and determines the receptor’s specificity

activated B cells, immunoglobulins, variable region, binds to the specific antigen and determines specificity, constant region, determines fate of the bound antigen by binding different Fc receptors on other immune cells

Antibodies are secreted by _______. Antibodies are ________ that are made of a ______ (which ________) and a _______ (which _________).

internal proteins, normal protein degradation, MHC molecule, no response to normal self epitopes, T-cell mediated killing for foreign epitopes, already primed

All cells express epitopes of their _______ on the cell membrane. These come from _______ and they are displayed in a _______ that is recognised by the T cell receptor. If a T cell has a receptor for the epitope, two things can happen: ________ or _______ (only if ______).

learn not to react to self antigens, learn to react against a unique antigen

T cells go though two rounds of education. Step 1: _______, then step 2: _______.

unique antigen, destroyed or deactivated, naive cells, inactive cells that recognise a foreign antigen

T cell precursors recognise a ______, and those that recognise self molecules are _______. The end result is ______, which are _______. This is most of the T cells in the blood.

antigen appears, effector cells, activated cells ready to act if the antigen is detected, temporary expansion of effector cells, specific for the same epitope

Naive cells are only activated if their _______. The end result is ______, which are ________. There is ______ that are _______.

display antigens from other cells in complex with their own MHC molecules, costimulation, activating coreceptors that trigger T cell proliferation, cytokines that turn on the right gene program to eliminate the target

Dendritic cells ________ to show naive T cells their antigen target is present. DCs tell cells what to do when they see their antigen by providing _______ by expressing ________ and secreting _______.

helper T cells (Th), secrete cytokines that help other immune cells, Th1, abnormal self cells, Th2, abnormal cell types

CD4+ T cells are ______ that _______. Dendritic cells prime different CD4+ T cells to respond to different types of antigens: _____ respond to _______ and ______ respond to ______.

cytotoxic T cells (Tc), kill cells expressing their target antigen, targeted and controlled, immune synapse, tight connection between target and immune cells, perforin, granzyme B

CD8+ T cells are _______ that _______. This is _______ by creating an ________ (_________) where there can be release of _____ and _____.

Perforin

Enzyme that forms pores in the target cell membrane

Granzyme B

Enzyme that enters pores in target cell membranes and induces apoptosis

a localised protective response elicited by injury or destruction of tissues which serves to destroy, dilute, or wall off both the agent and the injured tissue

Inflammation is defined as…

immune cell proliferation, restore the tissues, returns to homeostasis, excessive immune proliferation, no functional restoration, chronic inflammation, immunosuppression, tumourigenesis, mutations in the tumour prevent resolution

During acute inflammation, danger signals (e.g. from a microbe) causes ________ to ______, then the immune response ______. During chronic inflammation, danger signals (e.g. from a tumour) causes ________ but there is _______ leading to ______, ______, and _____ because _______.

progressive shift in cells present in a location, repetitive cycles of tissue healing and remodelling

Chronic inflammation leads to a ________ and creates ________. This affects risk and prognosis.

promoting DNA damage and preventing mutation correction, promoting cell proliferation, and creating a permissive microenvironment that promotes angiogenesis and prevents apoptosis

Inflammation drives cancer by several mechanisms:

STAT3, NFkB, and ROS/HIF1a

There are 3 critical signalling pathways in inflammation:

STAT3, cyclins, MYC, BCL-2/BCL-XL

NFkB activates _______, which activates _____, _____, and _____ that drive proliferation and block apoptosis.

E-cadherin, cell differentiation, EMT

NFkB and STAT3 inhibit _____ (which functions in _____), thus promoting _____.

hypoxia, NFkB signalling

HIF1a can be upregulated by _____ AND _____.

highly secretory cells, phagocytic, peripheral or resident macrophages altered by the TME, accumulate at hypoxic sites and the tumour edge, cytotoxic T cell suppression, secreting factors that inhibit immunity and promote tumour growth

Macrophages are _______ which are ______. Tumour-associated macrophages (TAMs) are derived from ________ and they ________. They cause ________ by ________.

regulate tissue homeostasis, inhibit immune activation, upregulating Arg1, enzyme that removes arginine from the TME that T cells need to function, upregulating iNOS, enzyme that produces nitric oxide which inactivates T cells, regulatory T cells

Myeloid-derived suppressor cells (MDSCs) normally ________ and they ______ by ______ (which is an _________) and _____ (________). They also activate ______ which are meant to inhibit T cell response.

releasing inhibitory cytokines for CD8+ T cells, releasing enzymes that kill CD8+ T cells, depriving CD8+ T cells of nutrients, and inhibiting DC maturation and function

Regulatory CD4+ T cells inhibit anti-tumour immunity by:

release factors that can regulate epithelial barrier or change overall metabolic processes, cancer growth, immunity, treatment efficacy

The microbiota has both local and distant effects that are mostly protective. In cancer, bacteria _________ which affects _____, _____, and _____.

Dysbiosis

Imbalance of the microbiota characterised by loss of beneficial bacteria, overgrowth of harmful bacteria, or reduced microbial diversity

translocating across disrupted barriers into the body and activating immune responses, secrete genotoxins, ethanol metabolism byproducts, nitrosamine production, carcinogen activation

During dysbiosis, bacteria can promote inflammation by ______. Bacteria also _______ to compete with other bacteria, but this can also affect bodily cells. _____, ______, and ______ by bacteria further promote inflammation and tumour growth.

tumour-associated antigens

Cancers express _______, which result from mutations to normal self proteins.

mutation burden, more mutations, more mutations, more TAAs, more immune detection, most mutations do not create TAAs, TAAs change over time in each tumour

Tumour ______ correlates with immunity as cancers with _______ respond better to immunotherapy. This assumes _____ = _____ = _____, but this does not necessarily enable immune detection and allows the appearance of clinically detectable macrometastases because ______ and _____.

immunogenic cell death

TAAs are released via…

elimination, equilibrium, and escape

The phases of immunity in cancer are:

effective immune recognition and killing of tumour cells, strong adaptive immune response

During the elimination immunoediting phase, there is _______ and _______. This is where we spend most of our lives.

evolution of new immune-resistant subclones, no tumour growth

During the equilibrium phase, immune recognition and killing of cancer cells is balanced by ________ and there is ______.

no longer recognises or kills tumour cells, actively suppresses or evades immune recognition, increased inflammation

During the escape phase, the immune system _________ and the tumour ______. There is ______ and tumour growth.

tumour evolution and heterogeneity, immune cells eliminate sensitive subclones allowing for creation of resistant subclones that can evolve and progress

Immunoediting drive _________ because…

low immunogenicity (e.g. loss of MHC), tumour treated as self antigen (in absence of co-stimulation TAAs are taken and presented by DCs to tolerise T cells), antigenic modulation selecting for variants without TAAs, tumour-induced immune suppression, and creation of a tumour-induced privileged site

Immune escape mechanisms by tumours include:

camouflage, coercion (prevent immune cell activation), cytoprotection (directly block attack)

The 3 groups of the hallmarks of cancer immune evasion are:

decreasing MHC expression so antigens are not presented to immune cells, decreasing immune cell recruitment

The camouflage immune evasion hallmark is most often achieved by _______, but can also be created by _______.

decreasing innate signalling, turn off expression of DAMPs to prevent interferon activation, preventing immune cell activation, starving immune cells and preventing their activation

The coercion immune evasion hallmark involves ________— tumours ______ to prevent immune recruitment, thus ________. Coercion can also involve the tumour ________

Fas/FasL, cell expressing FasL kill cells with Fas, upregulate soluble Fas as a decoy to block killing by T cells, upregulate FasL to induce killing of T cells

Cytoprotection of cancer cells often involves the _____ system which is a normal T cell killing mechanism wherein ___________. Cancer cells __________ and also __________.

upregulating T cell inhibiting molecules, inhibitory checkpoint molecules, turn off their activity, PD1 and CTLA4, upregulate checkpoint receptors, priming and effector

Cytoprotection can be carried out by ________. Normal activated T cells express _______ that _____ (e.g. ______). Tumours ________ that can inhibit cells in both _______ phases.

oncogenic mutations, oncogene or tumour suppressor mutation confers endogenous resistance to immune detection, immune resistant subclones are selected by the body’s attempt to kill the tumour cells (immunoediting)

Immune escape mechanisms can be driven by _______. There can be innate resistance (i.e. __________) or acquired resistance (i.e. __________).

downregulation of MHC

Loss of TP53 in a tumour can result in ______, making the tumour less susceptible to immune attack.

upregulate immune suppressive cytokines, downregulate interferon response genes, upregulate inhibitory immune receptors

KRAS mutations can ______, ______, and ______ in tumours to block the immune system.

downregulation of MHC, inhibition of apoptosis

Activating STAT3 mutations in the tumour can cause ______ and _____, creating immune suppression.

turns on “bad” immune cells, turns off “good” immune cells

When MYC is activated in a tumour, it _______ and ______ which creates an immune suppressive tumour environment.

neoantigen levels, PDL1, more neoantigens, immune response, interferon and PDL1 expression

DNA repair defects control ______ and ______. More mutations creates ______ which should correlate with ______. Consequences of losing DNA repair also influences…