55 Questions
Which step in the Cancer Immunity Cycle involves the release of cancer cell antigens?
Priming and Activation
What could be a reason for a tumor to be classified as a 'Cold tumour'?
Lack of T-cell attracting chemokines
Why may T cells not properly home to tumors according to the text?
Lack of chemokines in immune-excluded tumors
What is a characteristic of 'Immune-excluded tumours' based on the information provided?
Aberrant vasculature
Which step in the Cancer Immunity Cycle involves the trafficking of T cells to tumors?
Infiltration of T cells into Tumours
What could be a factor contributing to the immuno-suppression of effector cells in the tumor microenvironment?
Hypoxia and aberrant vasculature
What is a common characteristic of 'Cold tumours' based on the context provided?
Inadequate priming and defects in antigen presentation
What could contribute to a tumor being categorized as 'Immune-excluded'?
Stromal barriers and lack of chemokines
Why might DCs and T cells treat antigens as 'self' in cancer patients?
Tumor antigens may not be detected
What is the principal source of the extracellular matrix?
Fibroblasts
Which cells are associated with enhanced proliferative, migratory, and secretory properties in the tumor microenvironment?
Cancer-associated fibroblasts (CAFs)
Which type of lung cancer is the most common?
Non-small cell lung cancer
What do M2 Macrophages support within tumors?
ECM remodeling
Which factor is associated with T cell exclusion and poor response to anti-PD-L1 treatment?
TGFβ signature in CAFs
Which cells have been reported to enhance the recruitment of B cells through CXCL13 secretion?
Fibroblasts
What is the role of FAP+ CAF depletion in tumors?
Enhances T cell infiltration
'Loss-Of-Function CRISPR-Cas9 screening approach' aims to assess the impact of candidate genes on:
T cell exclusion
What do M1 Macrophages support within tumors?
Tumor regression
What is the role of fibroblasts in forming a physical barrier around tumors?
Limiting T cell and tumor cell interaction
What is the purpose of adding fibroblasts to the tumor islets in the study?
To measure the effects of fibroblasts on T cell exclusion
What does the 3D spheroid system aim to mimic?
Gradients of oxygen and nutrients found in tumors
What is the main advantage of using 3D techniques over traditional 2D cell cultures?
Replicates the microenvironment found in real tumors
Which CAF subtype expresses a high level of α-smooth muscle actin (αSMA) and resides closely to the tumor?
Myofibroblastic CAFs (myCAFs)
During which stage of lung adenocarcinoma do researchers observe a high presence of T cells and low presence of CAFs?
Early stages
What is the role of antigen-presenting CAFs (apCAFs) based on the text?
Expressing MHC II-related genes
How do researchers aim to exploit the plasticity of CAFs for therapeutic purposes?
By tilting the paradigm towards antitumorigenic CAF identities
What is one key feature of the necrotic zone mentioned in the text?
Dying cells
What is a distinctive characteristic of inflammatory CAFs (iCAFs) compared to other subtypes mentioned in the text?
Expression of chemokines and cytokines
What is one factor that differentiates 3D techniques from traditional 2D cell cultures according to the provided text?
Ability to establish physiological cell-to-cell contact
What is one advantage of using 3D techniques over traditional 2D cell cultures in mimicking the tumor microenvironment?
Creating gradients of oxygen and nutrients similar to real tumors
What is the primary purpose of adding fibroblasts to the tumor islets in the study described?
To promote T cell exclusion from the islets
How does the 3D spheroid system allow testing the effect of CAF-specific genes on T cell infiltration and tumor lysis effectively?
By hanging droplets of cells from a well
What role do antigen-presenting CAFs (apCAFs) play based on the provided text?
Expressing MHC II-related genes
What could be a potential consequence of inhibiting antigen-presenting CAFs (apCAFs) within the tumor microenvironment?
Reduced antigen presentation to immune cells
Which aspect of CAF plasticity is being explored for therapeutic purposes according to the text?
Exploiting antitumorigenic potential
What characteristic defines myofibroblastic CAFs (myCAFs) based on their location?
Residing closely to the tumor
What makes single-cell analysis studies essential in understanding CAF subtypes?
Revealing 3 major CAF subtypes
What could be a potential downside of inhibiting myofibroblastic CAFs (myCAFs) in tumors?
Reduced T cell localization near the tumor
What is the principal function of fibroblasts in the tumor microenvironment?
Supporting ECM remodeling
How can lung adenocarcinoma patients expressing high levels of TGFβ be more susceptible to treatment?
Depletion of cancer-associated fibroblasts
Which type of lung cancer is more aggressive and prone to metastasis compared to non-small cell lung cancer?
Small Cell Lung Cancer
What would be a potential consequence of inhibiting all roles of cancer-associated fibroblasts (CAFs) in the tumor microenvironment?
Immunosuppression
Why do small cell lung cancers have a higher metastatic potential compared to other lung cancer types?
Unique structural features promoting metastasis
What is the main role of M2 Macrophages within tumors according to the text?
Promote tumor growth and metastasis
How do circulating cancer-associated fibroblasts (CAFs) differ from typical fibroblasts?
Enhanced proliferative properties
What is the primary function of CXCL13 secreted by cancer-associated fibroblasts (CAFs)?
Enhance B cell recruitment
Why might fibroblasts around tumors pose a challenge for T cell and tumor cell interactions?
Collagen-rich barrier formation
What role do Cancer-associated fibroblasts (CAFs) play in immune checkpoint blockade therapy responsiveness?
Limiting immune effector cell recruitment
What might be a reason for the Cancer Immunity Cycle not performing optimally in cancer patients?
Inhibition of T cell infiltration into tumors
What is a characteristic of 'Cold tumors' based on the Cancer Immunity Cycle information?
Defects in cancer cell presentation
What scenario would lead to a tumor being categorized as 'Immune-excluded'?
Inhibiting T cells from infiltrating the tumor
What role do the factors in the tumor microenvironment play in suppressing effector cells?
Suppressing the effector cells that are produced
Which is a pattern associated with major T-cell infiltration in solid tumors?
High levels of stromal barriers and chemokines
Why might cancer patients face challenges with tumor antigens being detected by DCs and T cells?
DCs and T cells treating antigens as self
What plays a key role in the Recognition of Cancer Cells by T cells during the Cancer Immunity Cycle?
DCs treating cancer cell antigens as non-self
Study Notes
Cancer Immunity Cycle
- Generation of immunity is a cyclic process involving:
- Release of cancer cell antigens
- Cancer cell presentation (DCs/APCs)
- Priming and Activation (APCs + T cells)
- Trafficking of T cells to tumors (CTLs)
- Infiltration of T cells into tumors
- Recognition of cancer cells by T cells
- Ending with the killing of cancer cells, which increases cancer cell antigens and amplifies the process
Defects in Cancer Immunity Cycle
- In cancer patients, the cycle does not perform optimally due to:
- Tumor antigens may not be detected
- DCs and T cells may treat antigens as self-creating T regulatory cell responses
- T cells may not properly home to tumors and may be inhibited from infiltrating the tumor
- Factors in the tumor microenvironment might suppress the effector cells produced
T-cell Infiltration Patterns in Solid Tumors
- Major T-cell infiltration patterns observed:
- Cold tumor: lacks tumor antigen, inadequate priming, defects in antigen presentation, and/or lack of T-cell attracting chemokines
- Immune-excluded tumors: have immune evasion due to stromal barriers, lack of chemokines, aberrant vasculature, or hypoxia
Cancer-Associated Fibroblasts (CAFs)
- Abundant stromal cells in the tumor microenvironment
- Functional distinction from fibroblasts:
- Enhanced proliferative, migratory, and secretory properties
- More metabolically active, producing increased ECM factors
- Abnormal collagen production, often a more rigid and contractile pattern of collagen deposition
- Found in circulation, akin to circulating tumor cells (CTCs)
Role of CAFs in Regulating Tumor Immunity
- CAFs have multiple roles:
- Restricting the recruitment of immune effector cells such as CD8+ T cells into tumor tissues
- Central role in monocyte recruitment and the increased M2/M1 macrophage ratio
- CXCL13 secretion enhances the recruitment of B cells
- CAFs have both good and bad effects on cancer
CAFs and Tumor Immunity
- FAP+ CAF depletion/decrease induces T cell-mediated tumor regression
- CAF abundance is associated with poor prognosis
- TGFβ signature in CAFs: determinant of T cell exclusion and poor response to anti-PD-L1 (clinical trial)
Stromal Fibers and T Cell Infiltration
- Reduction in stromal fibers increases T cell infiltration and their contacts with tumor cell targets
- In some studies, depletion of CAFs results in immunosuppression and tumor progression
Lung Adenocarcinoma
- Leading cause of death from cancer in Canada
- 31,000 Canadians will be diagnosed with lung and bronchus cancer (13% of all new cancer cases in 2023)
- 20,600 Canadians will die from lung and bronchus cancer (24% of all cancer deaths in 2023)
- On average, 85 Canadians will be diagnosed with lung and bronchus cancer every day
Hypothesis and Aim
- Hypothesis: Cancer-associated fibroblasts (CAFs) play a key role in regulating T cell distribution at the tumor site
- Aim: Identify key CAF molecules that control/restrict T cell infiltration and target these factors to facilitate T cell infiltration and enhance anti-tumor adaptive immunity
Learn about the cancer immunity cycle process, including the release of cancer cell antigens, activation of T cells, trafficking of T cells to tumors, and killing of cancer cells. Understand how this cycle works and its implications for cancer patients.
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