Immune Surveillance & Tumor Defense

• Immune surveillance is a process where the immune system identifies and eliminates abnormal cells, preventing tumors and cancers.

Immune Checkpoints

• Immune checkpoints in specialized immune cells halt malignant cell growth before tumor replication.
• Tumors develop when malignant cells escape or go undetected by the immune system.

Host Defense Against Tumors

• The innate immune system provides the first line of defense against tumors by recognizing broad characteristics of tumor cells.
• The adaptive immune system uses specific antigen-dependent immune responses to stop tumor development.
• Immune surveillance is regulated by both innate and adaptive immune defenses.
• Natural killer (NK) cells bind to kill activation receptors and recognize HLA-B, C, and E for broad identification of malignant cells.
• Chemo and cell-mediated immune responses are induced when malignant cells are present.
• Lymphocyte activated killer (LAK) cells refer to NK cells attacking tumor cells when killer activation receptors are not halted by killer inhibitory receptors (KIRs).
• Target cells are lysed if KIR ligands on their surface do not halt killer activation receptors.
• NK cell activity proceeds if MHC class I molecule expression on the target cell surface is low, and KIR is not activated.

NK Cell Monitoring Process

• NK cells monitor the body for cancer, virally infected, and abnormal cells.
• Inhibitory receptors (including KIR) on NK cells bind to MHC class I molecules on healthy cells, sending a "don't kill" signal.
• Cancerous and virally infected cells downregulate MHC I to avoid cytotoxic T cells.
• Activating receptors (KAR) on NK cells recognize stress-induced ligands (MICA/MICB) or viral/cancer-associated antigens on abnormal cells, which triggers NK cell toxicity.
• NK cells kill target cells by:
  • Releasing cytotoxic granules containing perforin and granzymes, which induce apoptosis.
  • The Fas-FasL pathway, where NK cells express FasL that binds to the Fas receptor on target cells, triggering apoptosis.
  • Antibody-dependent cellular cytotoxicity (ADCC), where NK cells express CD16, which binds to the Fc region of antibodies that coat target cells leading to cell death.

Immune Cells in Epithelium Immunosurveillance

• NK cells, γ/δ T cells, CD4, and CD8 T cells are involved in the immunosurveillance of epithelium and mutated cell elimination.
• CD4+ T cells support CD8+ T cell activation by secreting cytokines like IL-2 and maintaining the antitumor immune response.
• CD8+ T cells recognize and destroy cells with abnormal or mutated peptides on MHC class I molecules.
• NK cells detect and kill cells with low or absent MHC class I expression via cytotoxic granules containing perforin and granzymes.
• Mast cells release histamine and cytokines to recruit other immune cells.
• Antigen-presenting cells like macrophages and dendritic cells engulf and digest antigens for presentation.

Tumor Development and Differentiation

• Development and differentiation of cells are regulated by increased concentrations of IL-2 cytokines.
• Macrophages secrete TNF cytokines, which stimulate tumor cell necrosis.
• Interferon cytokines increase MHC class I expression on tumor cells, improving NK cell recognition.

Adaptive Immune Response

• The adaptive immune response uses antibodies against specific tumor antigens on malignant cell surfaces.
• CTLs directly kill cells upon contact.
• Type IV hypersensitivity uses Th1 cells to recruit and activate macrophages and neutrophils, which attack and kill tumor cells.

Immune Surveillance Summary

• The immune system distinguishes between healthy and cancer cells.
• Tumor antigens are present on the plasma membrane and recognized by the immune system.
• Tumor antigens can be:
  • Mutational antigens, or mutated forms of normally expressed antigens.
  • Antigens produced by oncogenes or tumor suppressor genes.
  • Overexpressed antigens.
  • Viral antigens presented on the surface of virus-infected cells.
• Cancer cells are incorporated by antigen-presenting cells (APCs) that process and expose antigens.
• Helper T cells secrete stimulating factors for antibody production by B cells.
• Helper T cells activate macrophages, which engulf and eliminate cancer cells.
• Cytotoxic T cells directly recognize and destroy cancer cells.
• Cancer cells can escape immune system control by:
  • Secreting mediators that inhibit T cells or APCs.
  • Exposing modified antigens that are unrecognizable by the immune system.
• High levels of proliferation allow resistant forms to expand undisturbed, leading to immune tolerance.
• Immune surveillance plays a crucial role in controlling neoplastic growth.

NK Cell Recognition of Abnormal Cells

• NK cells recognize abnormal cells through surface receptors interacting with ligands on target cells, without prior sensitization.

Cancer Recognition

• NK cells express inhibitory receptors that recognize decreased MHC-I on cancerous cells.
• Examples include killer cell immunoglobulin-like receptors (KIRs) in humans and Ly49 receptors in mice.

Missing Self Recognition

• Abnormal cells often lack self-antigens, making them susceptible to NK cell recognition.
• Healthy cells interact with inhibitory receptors to prevent NK cell activation.
• Abnormal cells downregulate self-antigens, losing this inhibitory signal, and allowing NK cells to target them.

Activating Receptors

• NK cells express activating receptors that engage stress-induced ligands or pathogen-associated molecular patterns (PAMPs) on abnormal cells.
• Examples include NKG2D, NKp30, NKp44, and NKp46, which recognize MICA/B and ULBP on abnormal cells.

Immunologic Synapse Formation

• NK cells form an immunologic synapse upon recognizing abnormal cells.
• The immunologic synapse facilitates the release of cytotoxic granules (perforin and granzymes) toward the target cell, inducing cell death.

Role in Controlling Viral Infections

• NK cells are crucial in the early defense against viral infections by monitoring decreased MHC-I.
• Virally infected cells may exhibit altered surface antigens or downregulate MHC-I, triggering NK cell activation.

Release of Cytotoxic Granules

• Perforin creates pores in the target cell membrane, allowing granzymes to enter and trigger apoptosis.
• The release of cytotoxic granules by NK cells leads to the destruction of abnormal cells.