Guest Lecture: Cancer + CAFs
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Questions and Answers

Which step in the Cancer Immunity Cycle involves the release of cancer cell antigens?

  • Recognition of Cancer Cells
  • Trafficking of T cells to Tumours
  • Priming and Activation (correct)
  • Cancer cell presentation

    • What could be a reason for a tumor to be classified as a 'Cold tumour'?

  • Lack of T-cell attracting chemokines (correct)
  • Major T-cell infiltration
  • Defects in antigen presentation
  • Immune evasion due to stromal barriers

    • Why may T cells not properly home to tumors according to the text?

  • Lack of chemokines in immune-excluded tumors (correct)
  • Factors in the tumor microenvironment might suppress the effector cells
  • DCs and T cells treat antigens as self
  • Tumor antigens may not be detected

    • What is a characteristic of 'Immune-excluded tumours' based on the information provided?

    <p>Aberrant vasculature</p> Signup and view all the answers

    Which step in the Cancer Immunity Cycle involves the trafficking of T cells to tumors?

    <p>Infiltration of T cells into Tumours</p> Signup and view all the answers

    What could be a factor contributing to the immuno-suppression of effector cells in the tumor microenvironment?

    <p>Hypoxia and aberrant vasculature</p> Signup and view all the answers

    What is a common characteristic of 'Cold tumours' based on the context provided?

    <p>Inadequate priming and defects in antigen presentation</p> Signup and view all the answers

    What could contribute to a tumor being categorized as 'Immune-excluded'?

    <p>Stromal barriers and lack of chemokines</p> Signup and view all the answers

    Why might DCs and T cells treat antigens as 'self' in cancer patients?

    <p>Tumor antigens may not be detected</p> Signup and view all the answers

    What is the principal source of the extracellular matrix?

    <p>Fibroblasts</p> Signup and view all the answers

    Which cells are associated with enhanced proliferative, migratory, and secretory properties in the tumor microenvironment?

    <p>Cancer-associated fibroblasts (CAFs)</p> Signup and view all the answers

    Which type of lung cancer is the most common?

    <p>Non-small cell lung cancer</p> Signup and view all the answers

    What do M2 Macrophages support within tumors?

    <p>ECM remodeling</p> Signup and view all the answers

    Which factor is associated with T cell exclusion and poor response to anti-PD-L1 treatment?

    <p>TGFβ signature in CAFs</p> Signup and view all the answers

    Which cells have been reported to enhance the recruitment of B cells through CXCL13 secretion?

    <p>Fibroblasts</p> Signup and view all the answers

    What is the role of FAP+ CAF depletion in tumors?

    <p>Enhances T cell infiltration</p> Signup and view all the answers

    'Loss-Of-Function CRISPR-Cas9 screening approach' aims to assess the impact of candidate genes on:

    <p>T cell exclusion</p> Signup and view all the answers

    What do M1 Macrophages support within tumors?

    <p>Tumor regression</p> Signup and view all the answers

    What is the role of fibroblasts in forming a physical barrier around tumors?

    <p>Limiting T cell and tumor cell interaction</p> Signup and view all the answers

    What is the purpose of adding fibroblasts to the tumor islets in the study?

    <p>To measure the effects of fibroblasts on T cell exclusion</p> Signup and view all the answers

    What does the 3D spheroid system aim to mimic?

    <p>Gradients of oxygen and nutrients found in tumors</p> Signup and view all the answers

    What is the main advantage of using 3D techniques over traditional 2D cell cultures?

    <p>Replicates the microenvironment found in real tumors</p> Signup and view all the answers

    Which CAF subtype expresses a high level of α-smooth muscle actin (αSMA) and resides closely to the tumor?

    <p>Myofibroblastic CAFs (myCAFs)</p> Signup and view all the answers

    During which stage of lung adenocarcinoma do researchers observe a high presence of T cells and low presence of CAFs?

    <p>Early stages</p> Signup and view all the answers

    What is the role of antigen-presenting CAFs (apCAFs) based on the text?

    <p>Expressing MHC II-related genes</p> Signup and view all the answers

    How do researchers aim to exploit the plasticity of CAFs for therapeutic purposes?

    <p>By tilting the paradigm towards antitumorigenic CAF identities</p> Signup and view all the answers

    What is one key feature of the necrotic zone mentioned in the text?

    <p>Dying cells</p> Signup and view all the answers

    What is a distinctive characteristic of inflammatory CAFs (iCAFs) compared to other subtypes mentioned in the text?

    <p>Expression of chemokines and cytokines</p> Signup and view all the answers

    What is one factor that differentiates 3D techniques from traditional 2D cell cultures according to the provided text?

    <p>Ability to establish physiological cell-to-cell contact</p> Signup and view all the answers

    What is one advantage of using 3D techniques over traditional 2D cell cultures in mimicking the tumor microenvironment?

    <p>Creating gradients of oxygen and nutrients similar to real tumors</p> Signup and view all the answers

    What is the primary purpose of adding fibroblasts to the tumor islets in the study described?

    <p>To promote T cell exclusion from the islets</p> Signup and view all the answers

    How does the 3D spheroid system allow testing the effect of CAF-specific genes on T cell infiltration and tumor lysis effectively?

    <p>By hanging droplets of cells from a well</p> Signup and view all the answers

    What role do antigen-presenting CAFs (apCAFs) play based on the provided text?

    <p>Expressing MHC II-related genes</p> Signup and view all the answers

    What could be a potential consequence of inhibiting antigen-presenting CAFs (apCAFs) within the tumor microenvironment?

    <p>Reduced antigen presentation to immune cells</p> Signup and view all the answers

    Which aspect of CAF plasticity is being explored for therapeutic purposes according to the text?

    <p>Exploiting antitumorigenic potential</p> Signup and view all the answers

    What characteristic defines myofibroblastic CAFs (myCAFs) based on their location?

    <p>Residing closely to the tumor</p> Signup and view all the answers

    What makes single-cell analysis studies essential in understanding CAF subtypes?

    <p>Revealing 3 major CAF subtypes</p> Signup and view all the answers

    What could be a potential downside of inhibiting myofibroblastic CAFs (myCAFs) in tumors?

    <p>Reduced T cell localization near the tumor</p> Signup and view all the answers

    What is the principal function of fibroblasts in the tumor microenvironment?

    <p>Supporting ECM remodeling</p> Signup and view all the answers

    How can lung adenocarcinoma patients expressing high levels of TGFβ be more susceptible to treatment?

    <p>Depletion of cancer-associated fibroblasts</p> Signup and view all the answers

    Which type of lung cancer is more aggressive and prone to metastasis compared to non-small cell lung cancer?

    <p>Small Cell Lung Cancer</p> Signup and view all the answers

    What would be a potential consequence of inhibiting all roles of cancer-associated fibroblasts (CAFs) in the tumor microenvironment?

    <p>Immunosuppression</p> Signup and view all the answers

    Why do small cell lung cancers have a higher metastatic potential compared to other lung cancer types?

    <p>Unique structural features promoting metastasis</p> Signup and view all the answers

    What is the main role of M2 Macrophages within tumors according to the text?

    <p>Promote tumor growth and metastasis</p> Signup and view all the answers

    How do circulating cancer-associated fibroblasts (CAFs) differ from typical fibroblasts?

    <p>Enhanced proliferative properties</p> Signup and view all the answers

    What is the primary function of CXCL13 secreted by cancer-associated fibroblasts (CAFs)?

    <p>Enhance B cell recruitment</p> Signup and view all the answers

    Why might fibroblasts around tumors pose a challenge for T cell and tumor cell interactions?

    <p>Collagen-rich barrier formation</p> Signup and view all the answers

    What role do Cancer-associated fibroblasts (CAFs) play in immune checkpoint blockade therapy responsiveness?

    <p>Limiting immune effector cell recruitment</p> Signup and view all the answers

    What might be a reason for the Cancer Immunity Cycle not performing optimally in cancer patients?

    <p>Inhibition of T cell infiltration into tumors</p> Signup and view all the answers

    What is a characteristic of 'Cold tumors' based on the Cancer Immunity Cycle information?

    <p>Defects in cancer cell presentation</p> Signup and view all the answers

    What scenario would lead to a tumor being categorized as 'Immune-excluded'?

    <p>Inhibiting T cells from infiltrating the tumor</p> Signup and view all the answers

    What role do the factors in the tumor microenvironment play in suppressing effector cells?

    <p>Suppressing the effector cells that are produced</p> Signup and view all the answers

    Which is a pattern associated with major T-cell infiltration in solid tumors?

    <p>High levels of stromal barriers and chemokines</p> Signup and view all the answers

    Why might cancer patients face challenges with tumor antigens being detected by DCs and T cells?

    <p>DCs and T cells treating antigens as self</p> Signup and view all the answers

    What plays a key role in the Recognition of Cancer Cells by T cells during the Cancer Immunity Cycle?

    <p>DCs treating cancer cell antigens as non-self</p> Signup and view all the answers

    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

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    Description

    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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