L15 - Cancer Immunology Lecture 1 - Christoph Wuelfing Flashcards
1. Tumours need to activate resident innate immunity. How? 2. Dendritic cells need to activate adaptive immunity in the tumour draining lymph nodes. What do T cells recognise? 3. Innate and adaptive immune cells need to infiltrate tumours. Do they? Which immune cells do? 4. The tumour microenvironment interacts with the immune system. How?
Why is tumour immunology considered a challenging field to teach?
📚 Because it’s a dynamic, rapidly changing field with limited textbooks and reviews, relying heavily on primary literature.
Which immune cells are primarily responsible for killing tumour cells?
⚔️ Cytotoxic T cells and natural killer cells are the main killers in the tumour microenvironment.
What is the role of natural killer (NK) cells in tumour immunology?
🛡️ NK cells also kill tumour cells, though they are less prominent compared to cytotoxic T cells.
Why are myeloid cells such as macrophages and dendritic cells important in cancer immunity?
🔧 They shape the tumour microenvironment and support T cell activation, despite not directly killing tumour cells.
How does the tumour microenvironment impact immune responses?
🚧 The microenvironment is largely suppressive, which can hinder effective immune cell activity against tumours.
How is the tumour microenvironment largely suppressive?
🚧 The tumour microenvironment is suppressive because it accumulates immunosuppressive cells (e.g., regulatory T cells and myeloid-derived suppressor cells), secretes inhibitory cytokines (like TGF-β and IL-10), and expresses immune checkpoint molecules (e.g., PD-1, CTLA-4) that dampen effective T cell responses.
What is the significance of inhibitory receptors in the context of tumour immunology?
⛔ Inhibitory receptors (like PD-1 and CTLA-4) are upregulated during persistent stimulation and reduce immune cell function across various cell types.
Do inhibitory receptors affect only T cells?
🔒 No, they also modulate the function of other cells such as myeloid cells, impacting the overall immune response.
Why is understanding dendritic cell and macrophage biology crucial for tumour immunology?
💡 These cells define the environment in which cytotoxic T cells operate, influencing both activation and suppression of immune responses.
What key challenges must the immune system overcome to generate an effective antitumor response?
🛡️ The immune system faces several challenges:
- Activating Innate Immunity: Tumours must first trigger resident innate cells (like macrophages and dendritic cells).
- Priming Adaptive Immunity: Dendritic cells need to capture tumour antigens and migrate to tumour-draining lymph nodes to prime T cells.
- Immune Cell Infiltration: Both innate and adaptive immune cells (e.g., cytotoxic T cells) must be recruited from the blood into the tumour microenvironment.
- Adapting to a Suppressive Environment: Once inside, immune cells must overcome the inhibitory, suppressive signals of the tumour microenvironment to effectively eliminate tumour cells.
What makes the immune system in tumour immunology complex?
🧬 It involves a wide variety of cells—including dendritic cells, macrophages, neutrophils, mast cells, NK cells, T cells, and B cells—that work in concert to mount an antitumor response.
Why is it important to understand immune cell interactions in the context of tumour immunology?
🤝 Immune cells interact closely with one another, and these intercellular communications determine how effectively the immune system can recognize and attack tumour cells.
What does it mean that immune cells can acquire various differentiation states?
🔄 Each immune cell type can differentiate into distinct states (e.g., inflammatory vs. tissue-repair macrophages, Th1 (cell mediated) vs. Th2 (humoral immunity) vs. Th17 (Extracellular pathogens) CD4+ T cells), which influences their function during an antitumor response.
How does the dynamic nature of immune cell states impact tumour immunology?
⚡ Immune cell states are not static; they change in response to the tumour microenvironment, altering their behavior and effectiveness over time.
What is the significance of tumour cell dynamics in immunology?
🌀 Tumour cells are heterogeneous and evolve genetically, meaning the tumour is composed of diverse subpopulations that can adapt and potentially resist immune responses and therapies. ( selection)
Why is a systems-level view essential in understanding tumour immunology?
🔍 A holistic approach is required to integrate the complex interactions among various immune cells, their dynamic states, and the evolving tumour microenvironment for effective therapeutic targeting.
What does the diagram (“Tumour immunity is dynamic”) illustrate?
🔄 It shows how tumour cells and the immune system interact over time in three phases: elimination, equilibrium, and escape.
What happens during the “elimination” phase of tumour immunity?
🛡️ The immune system effectively identifies and destroys most nascent (early) tumour cells, preventing them from progressing.
Why are tumours described as heterogeneous and dynamic?
🌱 Because they contain diverse cell variants that continually acquire new mutations, some of which may resist immune attack.
What is the significance of the “equilibrium” phase?
⚖️ In this phase, the immune system kills some tumour variants while others survive and grow, creating a balance that exerts strong selection pressure on the tumour.
How does the tumour eventually “escape” immune control?
🏃 Tumour cells develop traits (e.g., immune suppression, altered antigens) that help them evade or subvert the immune system, leading to unchecked growth.
Why do clinical tumours pose a bigger challenge to the immune system?
🚧 By the time patients present with tumours, the cancer cells have already passed through immune selection, leaving behind the most immune-resistant variants.
How does this dynamic process influence cancer therapy?
🧩 Therapies must overcome the tumour’s evolved resistance mechanisms, targeting cells that have adapted to evade normal immune responses.
Why is it important to understand the immune system’s early success in tumour elimination?
💡 It highlights that many potential tumours never become clinically evident, and the ones we do see have already “outsmarted” the immune system, guiding us to design more robust treatments.
Why have mice traditionally been used in tumour immunology research?
🐁 Because they allow controlled experiments: researchers can inject mouse tumour cell lines, manipulate genes, and observe how the endogenous immune system responds, providing foundational insights.
What is a common approach in immunocompetent mouse models?
💉 Researchers inject tumour cell lines under the mouse’s skin, letting a solid tumour develop naturally. This allows the mouse’s immune system to mount an endogenous response, revealing how tumour and immunity interact.
What is the main advantage of immunocompetent mouse models?
🔬 They offer excellent experimental access. Scientists can create genetic variants and track how molecular determinants influence tumour growth and immune responses.
Why is it hard to fully replicate human tumours in mice?
🏷️ Human tumours often arise spontaneously over a long period, whereas many mouse models involve injecting tumour cells. Plus, mice are kept in sterile conditions, which alters their immune function compared to humans.
What modifications are sometimes made in mouse tumour models?
🧩 Researchers may use defined neo-antigens in tumour cells and matching TCR transgenic T cells. This setup clarifies which T cells recognize which antigens, offering more precise experimental control.
Why are immunodeficient mice used in some tumour experiments?
❌ They lack functional immunity, allowing researchers to inject human tumour cell lines without immediate rejection. Scientists can then introduce human immune cells (e.g., T cells) to study human-specific immune responses in a living organism.
What is the key limitation of immunodeficient mouse models?
🚧 Because these mice can’t mount their own immune response, you’re only observing the transferred human T cells and tumour cells, missing the broader complexity of a full immune system.
Why do researchers continue to refine mouse models despite their limitations?
⚖️ Mouse models still offer valuable insights—particularly in genetic manipulation and early discovery—although translation to humans requires caution and often additional human-focused studies.
What recent shift has occurred in tumour immunology research?
🔭 Researchers have moved from predominantly mouse-based studies to human-focused approaches that study patients’ own tumours and immune responses.
What are “Omics” approaches in studying human tumours?
🧬 They involve techniques like single-cell RNA sequencing, proteomics, and high-dimensional tissue staining to map all cell types and molecules within a tumour biopsy.
Why are human biopsy “Omics” approaches advantageous?
🌐 Because they examine endogenous tumours and endogenous immunity in real patients, providing a true snapshot of the ongoing immune response.
what does endogenous immunity refer to?
The immune responses and mechanisms that originate from within the body itself, including the body’s own cells, tissues, and molecules, rather than from external sources.
What is a major drawback of studying human tumour biopsies?
🚫 It’s difficult to manipulate the tumour or the immune system genetically in humans, limiting the ability to test specific experimental interventions.
what are tumour organoids, and why are they important?
🏗️ Tumour organoids are mini 3D cultures of a patient’s tumour (plus its immune cells). They preserve endogenous tumour-immune interactions while allowing some experimental manipulation.
Why is it challenging to maintain immune responses in organoids?
🔄 Because immune cells require continuous interaction with lymphoid organs (e.g., tumour-draining lymph nodes), which aren’t included in an isolated organoid.
What are in vitro tumour models like spheroids and organs on a chip?
🧩 They’re lab-based systems where tumour cell lines grow in 3D (spheroids) or microfluidic chambers (organs on a chip), often with added immune cells, enabling high experimental control.
What is a key limitation of these in vitro models (spheroids, organs on a chip)?
⚠️ Because they’re built from isolated components, it can be uncertain how well they replicate the complexity of in vivo human tumour immunity.
Why is studying immunity directly in humans ultimately important?
💉 The goal of immunology is to treat human disease, so understanding how the immune system naturally responds to tumours in patients is essential for developing effective therapies.
What changes in tissue induced by tumours are recognized by the immune system?
🔍 Tumour growth leads to tissue damage and the release of damage-associated molecular patterns (DAMPs), which alert the immune system to abnormal changes.
Which tissue-resident immune cells first detect tumour-induced changes?
👁️ Macrophages, monocytes and dendritic cells are the key tissue-resident cells that recognize these changes through pattern recognition receptors.
Besides DAMPs, what additional signals can activate the innate immune response in tumours?
🦠 In some cases, microbes such as bacteria may be present in tumours, providing additional danger signals that further activate immune responses.
What are the two possible outcomes following the initial immune response to tissue damage?
🔄 The immune response can lead to either tissue repair and elimination of nascent tumour cells or progress to chronic inflammation, which is often seen in established tumours.
How does the presence of microbes within tumours influence the immune response?
🌐 Even in areas considered sterile (e.g. melenoma and under the skin) , the unexpected presence of bacteria can trigger immune responses, adding complexity to the tissue damage signals and potentially influencing the balance between repair and chronic inflammation.
How does Fusobacterium nucleatum impact colorectal cancer prognosis?
🧫 Higher bacterial infiltration → Worse prognosis due to immune modulation.
What is the main trigger for the cGAS-STING pathway in tumour settings?
🧬 Cytoplasmic double-stranded DNA (e.g., from necrotic tumour cells or exosomes) activates cGAS, initiating this pathway.
Why does cytoplasmic DNA signal “danger”?
🚨 DNA is normally confined to the nucleus or mitochondria; finding it in the cytoplasm suggests infection or tumour cell damage, alerting the immune system.
What is cGAS, and what does it do?
⚙️ cGAS (cyclic GMP-AMP synthase) detects cytoplasmic dsDNA and synthesizes cGAMP from ATP and GTP.
How does cGAMP activate STING?
🚀 cGAMP binds to STING (stimulator of interferon genes) on the Golgi, causing STING tetramerization and triggering downstream signaling.
What is the key outcome of STING activation?
🏳️ Type I interferon production (e.g., IFN-β), which boosts innate immune responses and helps activate dendritic cells (DCs).
What happens when DCs are activated via cGAS-STING?
🌐 They can migrate to the draining lymph nodes, present tumour antigens, and prime T cells, linking innate detection to adaptive immunity.
What are other examples of “danger signals” besides dsDNA?
🔥 RNA (via TLR3), ATP (inflammasome activator), and extracellular F-actin (via DNGR1) can all signal tissue damage or infection
Why is the cGAS-STING pathway of therapeutic interest?
💡 Enhancing this pathway can boost antitumour immunity, making it a promising target for new immunotherapies.
What is MSA-2, and how was it discovered?
🧪 MSA-2 is a STING agonist identified through chemical compound library screening….. being explored as a potential therapeutic agent (specifically as a non-nucleotide STING agonist for cancer immunotherapy - shows promise in particular in combination with other therapies)
What structural feature of MSA-2 is necessary for STING activation?
🔗 Dimerization is required for STING binding and activation.
How is MSA-2 dimerization regulated?
⚖️ It is pH-dependent, requiring the acidic tumour microenvironment to become active.
why is the tumor microenvironment acidic?
The tumor microenvironment (TME) becomes acidic primarily due to the high metabolic activity and poor perfusion of tumors, leading to the accumulation of acidic byproducts like lactic acid and carbon dioxide.
Why is the pH dependency of MSA-2 important in drug design?
🎯 It ensures targeted activation in tumours, minimizing off-target effects in normal tissues.
What is the effect of orally administered MSA-2 in a mouse model?
🐭 It reduces tumour growth, demonstrating its potential as an immunotherapy.
hat is the role of migratory cDC1 cells in antitumor immunity?
🚀 cDC1 cells effectively prime CD8+ T cells in the draining lymph node, initiating an adaptive immune response.
What happens to cDC1 function over time?
⏳ cDC1 function diminishes over time, reducing the effectiveness of the antitumor immune response.
How can cDC1 function be restored to maintain CD8+ T cell priming?
🔄 Anti-CD40 and Flt3 signaling can restore cDC1 function, sustaining the immune response.
Why is continuous activation of dendritic cells necessary for an effective antitumor response?
🕒 A long-lasting immune response is required since antitumor immunity must persist for weeks or months to be effective.
What therapeutic approach has been shown to maintain cDC1 activation?
💉 Anti-CD40 antibody and Flt3 ligand therapy help sustain dendritic cell function and enhance CD8+ T cell priming.
How are tissue-resident macrophages (TRM) activated in tumors?
⚠️ TRMs are activated by danger signals and tumor-derived cytokines.
What process leads to the recruitment of monocytes to tumours?
🚨 Tumors trigger emergency myelopoiesis, leading to the recruitment of monocytes that differentiate into MDSCs (myeloid-derived suppressor cells) and TAMs (tumor-associated macrophages).
What is emergency myelopoiesis?
🚨Emergency myelopoiesis (EM) is the acute and rapid response of the hematopoietic system to an increased demand for mature myeloid cells, driven by signals like bone marrow ablation, infections, or sterile inflammation.
How does continous low-level macrophage activation affect macrophage phenotypes
🔄 In a metabolically competitive tumor environment, macrophages upregulate inhibitory receptors (PD-1, TIM-3) and generate ROS (reactive oxygen species), shifting from an immunostimulatory (M1) to an immunosuppressive (M2) phenotype (pro-inflammatory (M1) and anti-inflammatory (M2)
What is the impact of tumour-associated macrophages (TAMs) and MDSCs on immunity?
🚫 TAMs and MDSCs suppress T cell function and promote an immunosuppressive tumor microenvironment, aiding tumor growth and angiogenesis.
Why are tumor-associated macrophages (TAMs) challenging to target therapeutically?
❌ TAMs have proven highly resistant to therapeutic interventions, making it difficult to reverse their immunosuppressive effects.
How do bacteria inside tumours affect immune responses?
🧬 Unknown mechanisms alter immune responses to tumours, potentially influencing tumour progression and immune evasion.
If tumours arise from our own body, why do T cells recognise them?
🔥 Tumour cells express antigens not usually present in normal adult cells, breaking immune tolerance and making them visible to T cells.
What are the two main classes of tumour antigens?
🎭
1️⃣ Tumour-Associated Antigens (TAAs) – Normal proteins expressed abnormally (e.g., fetal proteins, differentiation antigens).
2️⃣Tumour-Specific Antigens (TSAs) / Neoantigens – Unique mutations in tumour cells.
What are Tumour-associated antigens?
👶 Normal human proteins re-expressed in tumours, often from fetal development (e.g., cancer-testis antigens, endogenous retroviruses).
What are tumour-associated antigens (TAA)? x2
🎭 Unmutated self-proteins that are abnormally expressed in tumours but may also be found in some normal tissues.
Can you name some common tumour-associated antigens?
🏥 Examples:
MAGE (Melanoma Antigen)
NY-ESO-1 (cancer germline antigens (CGA), expressed during
fetal development,)
MART-1 (Melanoma differentiation antigen)
Her2
What are cancer germline antigens (CGA)?
🍼 Proteins normally expressed only during fetal development but reactivated in tumours.
What are HERVs, and why are they relevant in cancer?
🦠 Human Endogenous retroviruses make up 8.5% of human DNA. Some are reactivated in cancer and can serve as tumour antigens.
What are tissue differentiation antigens (TDA)
🎯 Proteins expressed in specific tissue types and their derived tumours.
Can you name a well-known TDA?
🎨 MART-1 (Melan-A) – A melanocyte differentiation antigen expressed in melanoma.
What is HER2, and why is it significant?
⚡ HER2 is an overexpressed antigen in breast cancer and is targeted by therapies like trastuzumab (Herceptin).
What is carcinoembryonic antigen (CEA)?
🩸 CEA is an overexpressed tumour antigen found in colorectal and pancreatic cancers, used as a tumour marker.
Why are immune responses to TAAs weak?
⚠️ Since TAAs are self-proteins, the immune system has partial tolerance to them, making responses weak and less effective.
What makes tumour-specific antigens (neoantigens) unique?
💥 They arise from tumour-specific mutations and are not subject to immune tolerance, allowing stronger immune responses.
How are neoantigens generated?
🔄 Through mutations, insertions, deletions, or chromosomal rearrangements during tumour evolution.e.g. SNV = single nucleotide variants and INDEL = insertions and deletions
Why are neoantigens not shared between patients?
👥 Since each tumour acquires unique mutations, neoantigens are typically patient-specific.
Why are neoantigens attractive for therapy?
💊 Since they are not present in normal cells, therapies targeting neoantigens have high specificity and minimal side effects.
What is the biggest challenge in using neoantigens for therapy?
🛠️ Neoantigens are unique to each patient, requiring personalized therapy, which is complex and costly.
Do all tumours have the same number of mutations?
📊 No, tumours vary! Some, like lung and melanoma, have thousands of mutations, while childhood cancers tend to have fewer.
What was the methodology of the cancer genome atlas (TCGA) study
📊 RNA sequencing of 11,180 samples across 33 cancer types to analyze immune cell composition.
Why is immune cell composition important in cancer?
🔬 Different tumours have varying immune infiltrates, affecting response to therapy and survival.
How does immune composition affect patient survival
🔥 Inflammatory tumours (high TH1 & lymphocytes) → better survival
🧊 Immunosuppressive tumours (high TGF-β, regulatory T cells) → worse survival
How does tumour immune response differ between patients?
👥 Even within the same cancer type, patients have dramatically different immune infiltrate
Why does immune cell distribution within a tumour matter?
🔄 Segregated tumours (immune cells separate from cancer cells) → Poor immune response
🌀 Intermixed tumours → More effective immune attack
What was used to explore cell transcriptomes
🧬 Single-cell RNA sequencing is used to analyze 21 cancer cell types from 316 patients, examining 400,000 cells to explore their transcriptomes.
How were cells grouped based on their characteristics after having their transcriptomes exampled
🔍 Cells are clustered based on their phenotypes, with cells that are close to each other showing similar traits and those farther apart showing distinct traits.
How many subtypes are found for CDA T cells and CD4 T cells?
🔢 CDA T cells are divided into 16 subtypes, and CD4 T cells are divided into 21 subtypes.
What are the key T cell subtypes mentioned?
🦠 Key T cell subtypes include naive cells, memory cells, effector memory cells, tissue-resident memory cells, effector memory cells expressing CD5, and exhausted cells.
What is the role of effector memory cells in immune responses?
💪 Effector memory cells have the ability to carry out immune functions and generate new T cells, which is beneficial for an active immune response.
What are tissue resident memory cells and how do they function?
🏥 Tissue resident memory cells are memory cells that no longer travel through the body and are located in tissues, where they can help generate new T cells.
: What does the tumor microenvironment (TME) influence?
🌱 The tumor microenvironment can be immune-rich or immune-poor, and its composition significantly impacts tumor progression and treatment outcomes.
What are some characteristics of immune-rich tumors?
💉 In immune-rich tumors, immune cells can either mix or be separated. There is a wide variety of immune cells, and the balance between anti-tumor effectors and suppressive cells is crucial.
Why is the ratio of CDA T cells to Tregs important?
⚖️ A higher ratio of CDA T cells to Tregs in tumors is a good sign for prognosis, as Tregs are immunosuppressive.
What is the goal of cancer therapies targeting immune cells?
🎯 Therapy aims to bring immune cells into the tumor, ensure they are well-distributed, and achieve a favorable balance of effective versus regulatory immune cells.
What should be remembered for the exam about tumor immunology?
📚 Key topics include understanding the strengths and weaknesses of different models, the dynamics of tumor-immune coevolution, immune cell activation, key T cell subtypes, and the three stages of exhausted T cells.
What is immune exclusion?
🚫 Immune exclusion refers to the phenomenon where immune cells are unable to enter the tumor, preventing an effective anti-tumor immune response.
What does metabolic competition in the tumour microenvironment refer to?
🍩 Tumor cells, macrophages, and T cells compete for essential nutrients like glucose and glutamine, which impacts their ability to function properly and can suppress immune responses.
How do tumor cells and immune cells compete for glucose?
🍬 Tumor cells primarily metabolize glucose to lactate, a process called the Warburg effect, generating anabolic precursors but low ATP. This increases the acidity in the tumor environment, which suppresses immune cell function.
What role does glutamine play in tumor metabolism?
🔬 Glutamine is crucial for tumor cells, macrophages, and T cells as it feeds into the citric acid cycle to generate anabolic precursors needed for rapid cell proliferation.
How do metabolic constraints like low glucose and high lactate affect immune cells?
❌ Low glucose, high lactate, and low glutamine in the tumor microenvironment impair the function of immune cells, such as macrophages and T cells, by depriving them of key metabolic precursors.
What is the impact of low oxygen in the tumor microenvironment?
🌬️ Low oxygen in the tumor microenvironment does not severely hinder immune cell function, but it can affect the metabolic processes in tumor cells, making it part of the suppression mechanism.
