Cancer Immunology Quiz

Immune System and Cancer

• Cancer cells avoid immune destruction, escape the immune system, and exploit inflammation to promote tumor growth (cancer hallmarks).
• Cancer arises from activated oncogenes and loss-of-function (LOF) tumor suppressor genes (TSGs).
• Chronic inflammation contributes to approximately 20% of human cancers

Cancer as a Wound That Never Heals

• Rudolf Virchow linked inflammation and cancer in 1863, observing leukocytes in cancerous tissue.
• Research explores the transformative abilities of inflammation in cancer development.

Inflammation in Cancer

• Inflammation is the body's coordinated response to damaged cells or pathogens.
• Inflammation is often beneficial for fighting disease but can contribute to cancer progression in chronic forms.
• LOF mutations in inflammatory response components are less likely to be transmitted to offspring. This suggests a connection between the severity of inflammatory response and fertility.
• Inflammation is part of innate immunity
• Inflammation involves:
  • Cytokine/chemokine production (initiates immune response)
  • Increased vasodilation (enhances blood flow)
  • Leukocyte migration (attracts immune cells)
  • Activation of JAK-STAT pathway (triggered by cytokines)
  • ROS kinase production by macrophages, linked to tumorigenesis
  • Macrophages and neutrophils are common in cancer tissue
  • TNF cytokines activate ROS, a tyrosine kinase linked to tumor development
  • Cytokine production activates immunity and cancer inflammation

Acute vs. Chronic Inflammation

• Acute Inflammation: Short-term, typically resolves within six months, caused by infections (e.g., HPV, HepB), strong immune response, and no increased cancer risk.
• Chronic Inflammation: Long-term, persists without resolution, caused by persistent infections (e.g., HPV, HBV, HCV, H. pylori), or irritants (e.g., asbestos), weak immune response, increased cancer risk (contributes to ~20% of cancers).

Mechanisms Linking Chronic Inflammation to Cancer

• Immune Cell Actions in Tumors:
  • Cytokine secretion: Promotes cell proliferation (immune and cancer cells), inhibits apoptosis, activates telomerase, promotes angiogenesis, and induces DNA damage.
  • Supports cell movement, which aids metastasis.
• Tumor Microenvironment Effects:
  • Upregulates proliferation/survival pathways
  • Enables tissue remodeling and mutation accumulation
  • Promotes angiogenesis and metastasis.
• Chronic inflammation directly contributes to cancer by stimulating a response that inadvertently supports tumor growth.

Examples of Chronic Inflammation and Cancer

• Examples of infections linked to chronic inflammation and increased cancer risk include HPV, HBV, HCV, H. pylori, and asbestos exposure.

Inflammatory Response and Cancer Hallmarks

• Chronic inflammation can satisfy several cancer hallmarks by causing long-lasting inflammation, cytokine secretion (promoting immune activation and cell proliferation), inhibiting apoptosis, affecting telomerase for limitless replication, inducing blood vessel formation (angiogenesis), damaging DNA, and enabling metastasis.

Familial Adenomatous Polyposis (FAP)

• FAP is an inherited genetic defect in the APC gene.
• Animal models of FAP show increased colon polyps with germline mutations and when treated with DSS, a colon irritant.

Pro-inflammatory Cytokines (IL-1β, TNF-α, IFN-γ)

• Critical pro-inflammatory cytokines.
• COX enzymes synthesise prostaglandins:
  • COX1: Constitutive, involved in normal function.
  • COX2: Inducible, upregulated by cytokines, inflammation & carcinogenesis.
• COX2 overexpression is implicated in many cancers (breast, pancreatic, colon). It induces DNA damage, enhances cell proliferation, reduces apoptosis, and increases angiogenesis.
• Inhibiting COX2 can reduce tumor progression.

Rational Therapy: Targeting COX2

• NSAIDs, including COX2 inhibitors, can reduce inflammation and cancer risk.
• Regular aspirin use is linked with a 30% reduced risk of colorectal cancer and adenoma/invasive cancer prevention.

Nuclear Factor kappa B (NF-κB) and Cancer

• NF-κB is a crucial transcription factor involved in inflammatory responses, activated by pro-inflammatory cytokines.
• Overexpression or constitutive activation of NF-κB is common in cancer cells.
• NF-κB regulates cell proliferation and death balance during acute inflammation.
• NF-κB enhances survival by blocking cell death pathways.
• NF-κB activates signaling pathways in both cancer and tumor-associated inflammatory cells.

NF-κB Activation

• NF-κB is held in the cytoplasm by IkB, which masks the nuclear localization signal.
• IKK phosphorylates IkB, causing its dissociation from NF-κB.
• Phosphorylated IkB is degraded, freeing NF-κB to enter the nucleus.

Some NF-κB Target Genes

• TNF-α, IL-1, chemokines (drive inflammation), cyclin D1, c-myc (promote cell division), telomerase (limitless replication), BCL-XL (inhibits apoptosis), VEGF (promotes angiogenesis), TNF-α, IL-1, IL-8 (enhances blood vessel formation).

Rational Therapy: Targeting NF-κB Pathway

• IKKβ is essential for NF-κB activation.
• IKKβ deletion reduces cancer incidence and growth in mouse models.
• Inhibitors targeting IKKβ exhibit potential in chemotherapy and cancer prevention.

Cancer and Stem Cells

• Cancer can originate in committed stem cells or during daughter cell proliferation.
• Stem cell division types:
  • Asymmetric: One daughter cell differentiates, one remains a stem cell.
  • Symmetric: Two daughter cells become stem cells.
• Stem cells have unlimited replication ability and support tissue regeneration.
• Chronic inflammation and stem cells: repeated cycles of damage and regeneration, increasing the risk of mutation and malignant transformation.

FAP, an Inherited Genetic Defect in the APC Gene

• FAP results from an inherited APC gene mutation.
• Loss of APC function leads to increased cell proliferation and abnormal differentiation.
• In APC-deficient mice, DSS-induced colon inflammation leads to more polyps due to impaired differentiation during regeneration.

Cancer and Stem Cell Genes

• Hedgehog and Wnt pathways are crucial for stem cell self-renewal and are implicated in cancer development.
• Cancer may arise from stem cells that don't return to a resting state after tissue repair.

Hallmarks of Cancer

• Inflammation induces telomerase expression to maintain cell division; immune cells need continual proliferation to fight infection.
• NF-κB promotes cell cycle progression (cyclin D1) and inhibits apoptosis (blocking Rb-E2F), causing uncontrolled cell division.

Tumor Immunology: Early History

• William Coley linked bacterial infections to tumor regression, leading to the concept of immune surveillance and the use of BCG in bladder cancer therapy.

The Balance Between Host and Tumor

• Successful tumors evade immune surveillance by losing their immunogenicity and acquiring anti-immunogenic characteristics.

Checkpoint Blockade: PD-1/PDL-1 System

• The PD-1/PDL-1 system dampens T cell activity preventing autoimmune disease.
• Tumor cells upregulate PDL-1, evading immune detection.
• Blocking the PD-1/PDL-1 interaction with monoclonal antibodies reactivates T cells to fight cancer.

Chimeric Antigen Receptor (CAR)-T Cells

• CAR-T cells are genetically engineered T cells that target specific cancer antigens.
• These cells are effective at recognizing and destroying cancer cells.