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Microbiology
Table of Contents
Unit 19 Overview: Diseases of the Immune System
19.1 Hypersensitivities
19.2 Autoimmune Disorders
19.3 Organ Transplantation and Rejection
19.4 Immunodeficiency
19.5 Cancer Immunobiology and Immunotherapy

🦠microbiology review

19.5 Cancer Immunobiology and Immunotherapy

Citation:

Cancer immunobiology explores how our immune system recognizes and fights cancer cells. It's like a game of hide-and-seek, where immune cells search for unique markers on cancer cells to eliminate them.

The immune system's ability to detect cancer isn't perfect. Tumors can create a shield, making it hard for immune cells to do their job. That's why scientists are developing clever ways to boost our natural defenses against cancer.

Cancer Immunobiology

Recognition of cancer cells

  • Immune surveillance
    • Innate and adaptive immune cells constantly monitor tissues for signs of malignancy
    • Natural killer (NK) cells, dendritic cells (DCs), and T cells play crucial roles in detecting and eliminating transformed cells
  • Tumor-associated antigens (TAAs)
    • Cancer cells express unique or overexpressed antigens recognized by the immune system
    • Mutated proteins, cancer-testis antigens (NY-ESO-1), and differentiation antigens (CD19) serve as examples of TAAs
  • Antigen presentation and T cell activation
    • DCs capture and process TAAs, presenting them on major histocompatibility complex (MHC) molecules to T cells
    • CD8+ cytotoxic T lymphocytes (CTLs) recognize TAAs presented on MHC class I and directly kill cancer cells
    • CD4+ helper T cells recognize TAAs presented on MHC class II and secrete cytokines to support CTL and B cell responses
  • Antibody-mediated responses
    • B cells produce antibodies targeting TAAs on cancer cell surfaces
    • Antibodies induce antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) to eliminate cancer cells
    • Monoclonal antibodies (rituximab) and bispecific antibodies (blinatumomab) exemplify therapeutic antibodies in cancer treatment

Tumor Microenvironment and Immune Evasion

  • Immunosuppression in the tumor microenvironment
    • Cancer cells and stromal cells produce immunosuppressive factors (TGF-β, IL-10) that inhibit immune cell function
    • Regulatory T cells and myeloid-derived suppressor cells contribute to an immunosuppressive environment
  • Cancer stem cells
    • A subpopulation of tumor cells with self-renewal and differentiation capabilities
    • May be resistant to conventional therapies and contribute to tumor recurrence
  • Tumor-infiltrating lymphocytes (TILs)
    • Presence of TILs in tumors often correlates with better prognosis
    • Can be expanded ex vivo for adoptive cell therapy
  • Immunogenic cell death
    • Some cancer therapies induce immunogenic cell death, releasing danger signals and tumor antigens
    • Enhances immune recognition and response against the tumor

Effectiveness of immunotherapy approaches

  • Checkpoint inhibitors
    • Block inhibitory receptors (CTLA-4, PD-1) on T cells or their ligands (PD-L1) on tumor cells to restore T cell activation and effector functions
    • Effective in various cancers (melanoma, lung cancer) but not all patients respond
    • Potential for autoimmune-related adverse events (colitis, pneumonitis) due to non-specific immune activation
  • Adoptive cell therapy (ACT)
    • Infusion of ex vivo expanded and activated tumor-specific T cells
    • Chimeric antigen receptor (CAR) T cells engineered to target specific TAAs (CD19 for B cell malignancies)
    • Highly effective in certain hematological malignancies (leukemia, lymphoma) but limited success in solid tumors
    • Challenges include manufacturing complexity and toxicities such as cytokine release syndrome (CRS)
  • Oncolytic viruses
    • Genetically modified viruses (herpes simplex virus, adenovirus) that selectively replicate in and lyse cancer cells
    • Can induce anti-tumor immune responses by releasing TAAs and danger signals
    • Limited efficacy as monotherapy; often combined with other immunotherapies (checkpoint inhibitors)
    • Safety concerns related to viral replication and spread

Cancer Vaccines

Preventive vs therapeutic cancer vaccines

  • Preventive cancer vaccines
    • Administered to healthy individuals to prevent cancer development
    • Target viral antigens associated with cancer-causing viruses
      1. Human papillomavirus (HPV) vaccines (Gardasil, Cervarix) prevent cervical, anal, and oropharyngeal cancers
      2. Hepatitis B virus (HBV) vaccines (Engerix-B, Recombivax HB) prevent liver cancer
    • Induce humoral and cellular immunity to prevent viral infection and subsequent malignant transformation
  • Therapeutic cancer vaccines
    • Administered to patients with existing cancers to stimulate anti-tumor immune responses
    • Target TAAs or neoantigens specific to the patient's tumor
    • Aim to activate and expand tumor-specific T cells and memory responses
    • Can be cell-based or non-cell-based
      • Cell-based: dendritic cell (DC) vaccines loaded with tumor antigens (sipuleucel-T for prostate cancer)
      • Non-cell-based: peptide (gp100 for melanoma), DNA, or RNA vaccines encoding tumor antigens
    • Personalized neoantigen vaccines based on individual tumor mutations are in clinical trials

Key Terms to Review (71)

Apoptosis: Apoptosis is a form of programmed cell death that occurs in multicellular organisms. It plays a crucial role in regulating immune responses and maintaining cellular homeostasis.
Benign: Benign refers to a condition, tumor, or growth that is not cancerous and does not invade nearby tissue or spread to other parts of the body. Benign tumors are generally considered less harmful than malignant tumors.
Cancer vaccines: Cancer vaccines are immunotherapies designed to elicit an immune response against cancer-specific antigens. They can be used prophylactically or therapeutically to target and destroy cancer cells.
Cancer: Cancer is a disease characterized by the uncontrolled division and spread of abnormal cells within the body. It can disrupt normal immune system functions and evade immune responses.
Cell cycle: The cell cycle is a series of stages that a cell goes through to divide and produce two identical daughter cells. It includes phases such as interphase, mitosis, and cytokinesis.
CD95 (Fas) cytotoxic pathway: CD95 (Fas) cytotoxic pathway is a mechanism of programmed cell death (apoptosis) initiated by the interaction of CD95 (Fas) receptor with its ligand, FasL. This pathway plays a critical role in regulating immune responses and maintaining immune system homeostasis.
Cell: A cell is the basic structural, functional, and biological unit of all living organisms. In microbiology, understanding cell behavior is crucial for studying diseases of the immune system, including cancer.
Cervarix vaccine: Cervarix is a vaccine specifically designed to protect against certain strains of the human papillomavirus (HPV), primarily types 16 and 18, which are associated with cervical cancer. It aims to reduce the incidence of HPV-related diseases in the reproductive system.
Contact inhibition: Contact inhibition is a regulatory mechanism that functions to keep cells from proliferating excessively by halting cell division when they come into contact with each other. This process is crucial for maintaining tissue architecture and preventing tumor formation.
Cytotoxic T cell: Cytotoxic T cells are a type of white blood cell that kills cancer cells, cells that are infected with viruses, or damaged cells. They play a crucial role in the immune system's ability to target and destroy harmful cells.
Cytokines: Cytokines are small proteins released by cells, especially those of the immune system, that have a specific effect on interactions and communications between cells. They play crucial roles in regulating immune responses and inflammation.
Dendritic cells: Dendritic cells are specialized antigen-presenting cells that play a crucial role in the initiation of the immune response. They capture, process, and present antigens to T cells, thereby bridging innate and adaptive immunity.
Gardasil vaccine: Gardasil is a vaccine designed to prevent infections by certain strains of the human papillomavirus (HPV), which can lead to cervical cancer and other HPV-related diseases. It is commonly administered to adolescents and young adults before they become sexually active.
Granzyme: Granzymes are serine proteases released by cytotoxic T cells and natural killer (NK) cells. They induce apoptosis in target cells to eliminate infected or cancerous cells.
Hepatitis B: Hepatitis B is a viral infection caused by the Hepatitis B virus (HBV) that affects the liver and can lead to both acute and chronic disease. It is primarily transmitted through contact with infectious body fluids.
Human papillomavirus (HPV): Human papillomavirus (HPV) is a group of related viruses, some of which can cause genital warts and cancers such as cervical cancer. It is one of the most common sexually transmitted infections globally.
Imlygic: Imlygic, also known as talimogene laherparepvec (T-VEC), is an oncolytic viral therapy used to treat melanoma. It uses a genetically modified herpes simplex virus to selectively infect and kill cancer cells while stimulating an anti-tumor immune response.
IL-12: IL-12 is a cytokine produced by dendritic cells, macrophages, and B-cells that plays a crucial role in the differentiation of naive T cells into Th1 cells. It is important for the immune response against intracellular pathogens and has applications in cancer immunotherapy.
Leukemia: Leukemia is a type of cancer that originates in blood-forming tissues, leading to the abnormal production of white blood cells. It disrupts the body's ability to fight infection and impairs normal blood cell function.
Major histocompatibility complex: The Major Histocompatibility Complex (MHC) is a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules in vertebrates. These proteins display antigen fragments to T cells, triggering an immune response.
Malignant: Malignant refers to the characteristic of cancer cells that are invasive and capable of spreading to other parts of the body. Unlike benign tumors, malignant cells can metastasize and often lead to serious health issues.
Melanoma: Melanoma is a type of skin cancer originating from melanocytes, the cells responsible for pigment production in the skin. It is known for its potential to spread to other parts of the body if not detected early.
Naïve helper T cells: Naïve helper T cells are a subset of T cells that have not yet encountered their specific antigen. They play a crucial role in the adaptive immune response by differentiating into various types of effector T cells upon activation.
NK cell: NK cells, or Natural Killer cells, are a type of lymphocyte critical for the innate immune response. They play a vital role in targeting and destroying virally infected cells and tumor cells without prior sensitization.
Perforin: Perforin is a protein released by cytotoxic T cells and natural killer (NK) cells that forms pores in the membranes of target cells, leading to cell lysis. It plays a critical role in the immune system's ability to eliminate infected or cancerous cells.
Prostate cancer: Prostate cancer is a malignant tumor that originates in the prostate gland cells. It can affect immune system functioning and response.
Reoviruses: Reoviruses are a family of double-stranded RNA viruses that can infect both humans and animals. They have been studied for their potential use in oncolytic virotherapy, where they selectively infect and kill cancer cells.
Reolysin: Reolysin is an oncolytic virus derived from the reovirus that selectively infects and destroys cancer cells. It is being studied as a form of immunotherapy to harness the immune system against tumors.
Rituximab: Rituximab is a monoclonal antibody used to target CD20 proteins on the surface of B cells. It is often used in the treatment of certain autoimmune diseases and lymphomas.
Rubeola: Rubeola, also known as measles, is a highly contagious viral infection caused by the measles virus. It primarily affects the respiratory system and can lead to serious complications if not properly managed.
Sipuleucel-T (Provenge): Sipuleucel-T (Provenge) is an autologous cellular immunotherapy used to treat metastatic prostate cancer. It involves using a patient's own immune cells that are modified to target and attack prostate cancer cells.
T-VEC: Talimogene laherparepvec (T-VEC) is an oncolytic viral therapy derived from the herpes simplex virus type 1, engineered to selectively infect and kill cancer cells while stimulating an anti-tumor immune response. It is administered via direct injection into tumors.
Tumor: A tumor is an abnormal mass of tissue that results from excessive cell division, which can be benign or malignant. Malignant tumors are cancerous and have the potential to invade surrounding tissues and spread to other parts of the body.
Tumor antigen: A tumor antigen is a molecule expressed on the surface of tumor cells that can be recognized by the immune system. These antigens are often used as targets in cancer immunotherapy.
Tumor-specific antigens: Tumor-specific antigens (TSAs) are unique proteins or molecules expressed on the surface of tumor cells but not found on normal cells. They can stimulate an immune response, making them targets for cancer immunotherapy.
T Cells: T cells, also known as T lymphocytes, are a type of white blood cell that play a crucial role in the adaptive immune response. They originate from stem cells in the bone marrow and mature in the thymus gland, developing specialized functions to recognize and eliminate threats to the body.
Dendritic Cells: Dendritic cells are a type of antigen-presenting cell that play a crucial role in the immune system. They act as sentinels, constantly surveying the body for signs of infection or disease, and are responsible for initiating and shaping the adaptive immune response.
Cytokines: Cytokines are a diverse group of small proteins secreted by various cells, primarily immune cells, that act as signaling molecules to coordinate and regulate immune responses, inflammation, and other physiological processes. They play a crucial role in cellular defenses, pathogen recognition, inflammation, adaptive immunity, and various immune-related disorders and conditions.
Major Histocompatibility Complex: The major histocompatibility complex (MHC) is a large gene complex that encodes proteins responsible for the regulation of the immune system in most vertebrates. It plays a crucial role in autoimmune disorders and the immune response to cancer by presenting foreign or abnormal peptides to T cells, triggering an appropriate immune reaction.
Immunosuppression: Immunosuppression refers to the reduction or inhibition of the normal immune response, either through natural means or through medical intervention. This can have significant implications in various areas of health and disease.
CD4+ Helper T Cells: CD4+ helper T cells are a type of T lymphocyte that play a crucial role in the adaptive immune response. They coordinate and orchestrate the activities of other immune cells, such as B cells and cytotoxic T cells, to mount an effective immune defense against pathogens and diseases, including cancer.
IFN-γ: IFN-γ, or interferon-gamma, is a critical cytokine involved in the regulation of the immune system and the body's response to cancer. It is a key player in the complex interplay between the immune system and cancer cells, playing a crucial role in cancer immunobiology and immunotherapy.
Antibody-Dependent Cellular Cytotoxicity: Antibody-dependent cellular cytotoxicity (ADCC) is an immune response mechanism in which antibodies bound to the surface of a target cell stimulate effector cells, such as natural killer cells, to destroy that target cell. It is an important process in the body's defense against cancer cells and virus-infected cells.
Rituximab: Rituximab is a monoclonal antibody used in the treatment of various types of cancer and autoimmune disorders. It specifically targets the CD20 antigen expressed on the surface of B cells, making it a crucial component of cancer immunobiology and immunotherapy approaches.
Blinatumomab: Blinatumomab is a bispecific T-cell engager (BiTE) antibody that simultaneously binds to CD3 on T-cells and CD19 on B-cells, effectively bringing the two cell types together to induce T-cell-mediated lysis of CD19-positive target cells. This mechanism of action makes blinatumomab a promising immunotherapeutic agent for the treatment of certain B-cell malignancies.
PD-L1: PD-L1, or Programmed Death-Ligand 1, is a protein that plays a crucial role in the regulation of the immune system and its interaction with cancer cells. It is a key component in the understanding of cancer immunobiology and the development of immunotherapeutic strategies to treat cancer.
Adoptive Cell Therapy: Adoptive cell therapy is a type of cancer immunotherapy that involves the transfer of a patient's own immune cells, which have been genetically modified or expanded ex vivo, back into the patient to enhance the immune system's ability to recognize and destroy cancer cells.
Cancer Stem Cells: Cancer stem cells are a small subpopulation of cells within a tumor that possess the unique ability to self-renew and differentiate into the diverse cell types that comprise the tumor. These cells are thought to be responsible for tumor initiation, progression, and resistance to treatment.
Checkpoint Inhibitors: Checkpoint inhibitors are a class of immunotherapy drugs that work by blocking immune checkpoint proteins, which are molecules that normally act as 'brakes' on the immune system. By releasing these brakes, checkpoint inhibitors enhance the body's immune response against cancer cells.
Cytokine Release Syndrome: Cytokine release syndrome (CRS) is a systemic inflammatory response that can occur as a severe side effect of certain cancer immunotherapies, such as chimeric antigen receptor (CAR) T-cell therapy. It is characterized by the rapid release of large amounts of cytokines into the bloodstream, leading to a cascade of physiological reactions that can be life-threatening if not properly managed.
Tumor-Infiltrating Lymphocytes: Tumor-infiltrating lymphocytes (TILs) are immune cells, specifically T cells, that have migrated into a tumor and play a crucial role in the body's immune response against cancer. These lymphocytes are a key component of the cancer immunobiology and immunotherapy landscape.
NY-ESO-1: NY-ESO-1 is a cancer-testis antigen that is expressed in various types of cancer cells but not in normal adult tissues, making it a promising target for cancer immunotherapy. It is a protein that is recognized by the immune system and can elicit an immune response against cancer cells expressing this antigen.
CD8+ Cytotoxic T Lymphocytes: CD8+ cytotoxic T lymphocytes, also known as killer T cells, are a type of T cell that play a crucial role in the body's immune response against cancer cells and cells infected by pathogens. These specialized lymphocytes have the ability to directly recognize and destroy target cells that display specific foreign or abnormal antigens on their surface.
Chimeric Antigen Receptor: A chimeric antigen receptor (CAR) is a synthetic receptor that is engineered by combining an antigen-binding domain, typically derived from an antibody, with signaling domains from T-cell receptors. This fusion allows T cells expressing the CAR to recognize specific tumor-associated antigens and mount an immune response against cancer cells.
Gardasil: Gardasil is a vaccine developed to prevent infection by certain strains of the human papillomavirus (HPV), which is the leading cause of cervical cancer and other HPV-related cancers and diseases. It plays a crucial role in both cancer immunobiology and the prevention of viral infections of the reproductive system.
Cervarix: Cervarix is a bivalent human papillomavirus (HPV) vaccine that protects against two strains of HPV, HPV-16 and HPV-18, which are responsible for the majority of cervical cancer cases. It is an important tool in the prevention and immunobiology of viral infections of the reproductive system, as well as cancer immunotherapy.
Tumor Microenvironment: The tumor microenvironment refers to the complex and dynamic ecosystem surrounding a solid tumor, which includes various non-cancerous cell types, extracellular matrix, blood vessels, and signaling molecules. This microenvironment plays a crucial role in cancer progression, metastasis, and response to treatment.
Immunogenic Cell Death: Immunogenic cell death (ICD) is a form of programmed cell death that elicits an immune response, leading to the activation and recruitment of immune cells to recognize and eliminate the dying cells. This process is particularly relevant in the context of cancer, where ICD can enhance the efficacy of cancer immunotherapies.
CD19: CD19 is a cell surface protein that serves as a co-receptor for the B-cell receptor (BCR) complex. It is expressed on the surface of B cells and plays a crucial role in the regulation of B-cell development, activation, and signaling.
Immune Surveillance: Immune surveillance is the process by which the immune system continuously monitors the body for the presence of abnormal or foreign cells, such as cancer cells or pathogens, and initiates an immune response to eliminate them. It is a critical component of the body's defense against disease and plays a crucial role in the context of cancer immunobiology and immunotherapy.
IL-2: IL-2, or Interleukin-2, is a cytokine that plays a crucial role in the regulation and activation of the immune system, particularly in the context of cancer immunobiology and immunotherapy.
Complement-Dependent Cytotoxicity: Complement-dependent cytotoxicity (CDC) is a mechanism by which the complement system, a part of the immune system, can directly lyse or kill target cells. This process involves the activation of the complement cascade, leading to the formation of a membrane attack complex that disrupts the target cell's membrane and causes cell death.
PD-1: PD-1, or Programmed Cell Death Protein 1, is an inhibitory receptor expressed on the surface of T cells, B cells, and other immune cells. It plays a crucial role in regulating the immune response and maintaining self-tolerance, making it a key player in both cancer immunobiology and immunotherapy.
CTLA-4: CTLA-4, or Cytotoxic T-Lymphocyte-Associated Protein 4, is a crucial immune checkpoint receptor that plays a pivotal role in regulating the activation and function of T cells, a key component of the adaptive immune system. This term is particularly relevant in the context of cancer immunobiology and immunotherapy, as well as in the production of polyclonal and monoclonal antibodies.
Engerix-B: Engerix-B is a recombinant hepatitis B vaccine developed by GlaxoSmithKline. It is designed to stimulate the immune system to produce antibodies against the hepatitis B virus, providing protection against infection.
Recombivax HB: Recombivax HB is a recombinant hepatitis B vaccine that is used to prevent infection with the hepatitis B virus. It is a critical tool in cancer immunobiology and immunotherapy, as it helps stimulate the immune system to recognize and fight against hepatitis B-related cancers.
Tumor-Associated Antigens: Tumor-associated antigens (TAAs) are proteins or other molecules that are present on the surface of cancer cells and are recognized as foreign by the immune system. These antigens are typically expressed at higher levels or in a different form on tumor cells compared to normal healthy cells, making them potential targets for cancer immunotherapy.
Oncolytic Viruses: Oncolytic viruses are a class of viruses that are designed or naturally occurring to selectively infect and destroy cancer cells, while leaving healthy cells unharmed. These viruses utilize the unique characteristics of cancer cells to replicate and spread, making them a promising approach in cancer immunobiology and immunotherapy.
Gp100: gp100, also known as glycoprotein 100, is a melanocyte differentiation antigen that is highly expressed on the surface of melanoma cells. It serves as a target for immunotherapeutic approaches in the treatment of melanoma, a type of skin cancer.
Natural Killer Cells: Natural killer (NK) cells are a type of cytotoxic lymphocyte that play a crucial role in the body's innate immune response. They are a key component of the cancer immunobiology and immunotherapy processes, capable of directly killing tumor cells without prior sensitization.
Sipuleucel-T: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. It is designed to stimulate an immune response against prostate cancer cells by using the patient's own immune cells to target specific antigens expressed on the surface of prostate cancer cells.