Lecture 10 - inflammation and immune avoidance Flashcards
Describe Inflammation vs. anti-tumour immunity
Immunity exerts anti-tumorigenic function by immunosurveillance and sculpting of tumour heterogeneity.
At the same time pro-tumorigenic inflammation promotes cancer by blocking anti-tumour immunity.
Inflammation shapes the tumour microenvironment, drives tumour-promoting signals.
Consequence: the immune system can play significant pro- and anti-tumorigenic roles at all stages of tumorigenesis.
Immunity – anti-tumourigenic function through immunosurveillance
Inflammation promotes cancer
Much of this orchestrated through different cytokines
Describe the anti-tumorigenic role of the immune system
Endogenous response to transformed and cancerous cells.
Used in implementation of emerging immunotherapies: these redirect/activate the immune system to recognise and kill cancer cells.
Examples: checkpoint blockade, vaccines, chimeric antigen receptors (CARs).
Stratification of tumours based on infiltration of T cells and other components required for anti-tumour immune function.
But: the immune system can be pro-tumorigenic – up-regulation of other factors, cell types promoting inflammation.
Stratifying the cancer based on infiltration of T cells
More t cells getting into tumour might be good thing - might be possible to activate those T cells to attack tumour and benefit patient
But immune system can be pro tumorigenic
Describe Cancer-promoting inflammation
Inflammation and tissue repair immune responses enhance tumour incidence, growth, and progression.
NSAIDs, e.g. aspirin, associate with reduced cancer incidence and mortality.
Inflammatory mechanisms important for tissue repair can also promote tumorigenesis.
Inflammatory mechanisms that aspirin might be inhibiting are important not only for tissue repair but also for tumourigenesis
Risk of metastasis much lower when taking aspirin
Evidence aspirin slows disease progression
Describe Feed-forward loop of inflammation-induced signalling
Unlike inflammation during tissue regeneration, tumour inflammation does not resolve.
Hematopoietic-derived cellular precursors are recruited to the tumour microenvironment by heterotypic signalling.
Activation of macrophages, monocytes, neutrophils or innate lymphoid cells to the tumour results in pro-proliferative cytokine production.
Positive feedback loop
Unlike inflammation in tissue regeneration, inflammation in the context of the tumour doesn’t resolve it just keeps going – results in pro-proliferative cytokine production – immune cells are activated to release cytokines and chemokines which then promote tumour formation
In normal inflammatory response there is injury to the epithelium, epithelium becomes inflamed, this results in recruitment and activation of immune cells which release cytokines – feed back on and orchestrate an immune response, includes proliferation and epithelial restoration
Oncogenic event – also recruit immune cells- excessive proliferation and no restoration -> chronic inflammation and immunosuppression
What are causes of cancer inflammation?
Cancer-associated inflammation can occur at different points during tumour development.
Before carcinogenesis: autoimmunity (obesity, type 2 diabetes), infection (H. pylori)
Driven by cancer cells or anti-cancer chemotherapy.
Multiple causes, e.g. persistent oncogene-induced stress, cell death, hypoxia, etc.
Describe therapy-induced cancer inflammation
Inflammation occurs in response to chemotherapy and radiotherapy.
Release of damage-associated molecular patterns (DAMPs), e.g. ATP, from dying cancer cells (necrosis).
Complex consequences: may promote T cell responses or may be immunosuppressive.
Production of cytokines, TNF, EGF, IL-6, Wnt ligands may recruit myeloid cells and fibroblasts (inflammation resembling response to injury), resulting in tumour progression.
Inflammation occurs through release of DAMPs
Therapy targets tumour, generates necrotic products which activate immune cells, which then release cytokines which promote tumour and may promote resistance to therapy
Describe Causes of inflammation during tumorigenesis
Loss of functional p53 results in increased expression of NF-kB-dependent inflammatory genes.
Oncogenic K-Ras regulates the chemokine CXCL3 required for myeloid cell recruitment.
K-Ras and c-Myc activation co-operatively induce CCL9 and IL-23 in pancreatic tumours.
Tumorigenic pathogens (e.g. HBV, HCV, HPV) will promote inflammatory responses.
Commensal microbiota may promote inflammation by adhering to cancer cells or release of proinflammatory microbial metabolites, e.g. in colon cancer.
Describe tumour initiation
Macrophages and neutrophils produce ROS which can induce mutagenesis within tissues, leading to cellular transformation.
Chronic intestinal inflammation leads to accumulation of mutations in Tp53.
Cytokines (e.g. IL-1β) released by inflammatory cells can activate epigenetic changes in epithelial cells (histone modifications, miRNA, lncRNA) which promote tumorigenesis.
Inflammation – leads to release of ROS/RNI, causes mutations -> tumour initiation
Describe tumour promotion
Inflammatory mediators can promote tumour growth and plasticity.
NF-kB in immune cells regulates release of cytokines (e.g. IL-6, IL-11, IL-17) promoting cancer cell survival and proliferation (heterotypic signalling).
Inflammatory cells can stimulate angiogenesis and fibroblast recruitment.
Inflammatory signals can alter the ECM and availability of key tumour-promoting metabolites.
Describe metastasis
Inflammation can promote invasion, migration and EMT.
TNF and IL-1β can affect EMT-inducing transcription factors Slug and Twist.
IL-11 can recruit cancer-associated fibroblasts which can support invasion and immune escape.
In breast cancer, IL-11 acts on cancer cells to drive selection of the most invasive clones.
Recruitment of myeloid cells to the invasive perimeter leads to MMP production.
EMT-inducing txn factors can push carcinoma cells from epithelial-like state into more mesenchymal-like invasive migratory phenotype
Describe Intravasation and extravasation
Inflammatory cytokines are potent inducers of integrins, selectins and adhesion molecules, e.g. VCAM-1, ICAM-1.
Potential regulation of site-specificity.
Monocytes and neutrophils can aid adherence of CTCs at secondary sites permitting extravasation.
IL-17-dependent neutrophil activation drives breast cancer metastasis through cellular interactions and production of a pre-metastatic niche.
Inflammatory cytokines can promote expansion of dormant micrometastases.
If cytokines activate different repertoire of adhesion molecules that could impact site specificity
Describe Inflammation and cell plasticity
NF-kB inflammatory signalling can cause dedifferentiation to CSCs within the TME.
Other cell types in the TME influence and drive plasticity.
Cancer cells can use vesicular transport to shape dendritic cell plasticity, regulating T cell responses.
Macrophages can polarise to tumour-promoting (TAMs) or tumour-ignorant phenotypes dependent on cytokine signalling repertoire.
Describe immune surveillance
Three phases: elimination, equilibrium, escape.
Elimination: innate and adaptive immune responses control/inhibit tumour growth.
Secretion of proinflammatory cytokines (IL-12 and IFN- γ), killing by innate immune cells, e.g. NK cells, DCs and macrophages. DCs activate tumour-specific CD4+ and CD8+ T cells.
Equilibrium: Cancer cells are eradicated, or clonal variants can develop resistance by decreasing immunogenicity and/or producing immunosuppressive factors.
Escape occurs if the immune system can’t eliminate these cells and the tumour grows.
Describe mechanisms of immune evasion
Low immunogenicity, e.g. secretion of TGF-β, IL-10, indoleamine 2,3-dioxygenase (IDO).
Extracellular matrix hindrance.
Expression of immune inhibitory co-stimulatory receptors (checkpoints), e.g. PD-1, CTLA-4
Infiltration of suppressive immune cells, e.g. Tregs, tumour-associated macrophages.
Inflammatory cells and cytokines in tumours are more likely to be immunosuppressive than induce anti-tumour responses.
Balance between tumour-promoting and tumour-antagonising microenvironment is a potential therapeutic target
Describe how MYC regulates immune suppression
MYC and Ras cooperate to drive tumorigenesis.
KRasG12D mouse lung cancer model: co-activation of MYC drives proliferative and invasive tumours with a highly inflammatory and immune-suppressed stroma.
IL-23 and CCL9 are cell non-autonomous effectors of MYC-driven lung carcinogenesis.
CCL9 mediates recruitment of macrophages, angiogenesis, and expulsion of T and B cells.
IL-23 orchestrates exclusion of adaptive T and B cells and innate immune NK cells.
