Cancer Immunology Flashcards
Cancer cells have defects…
in regulatory circuits that control normal cell proliferation and homeostasis
*Inappropriate expression or mutations of factors (e.g., oncogenes and tumor suppressor genes) that normally control these processes is associated with the cancerous state.
What are the Malignant Tumor Classifications?
- carcinoma
- leukemias and lymphomas
- sarcomas
carcinoma
(>80%) - arise from epithelial cells in skin, epithelial lining of internal organs and glands (e.g., colon, breast, prostate, lung, mouth, salivary glands, tongue); 90% of all oral cancers are squamous cell carcinomas
Leukemias and lymphomas
(9%) - malignant tumors of hematopoietic cells of bone marrow; leukemias are single cells and lymphomas tumor masses. Lymphomas can also occur in the mouth and can derive from tonsils/ adenoids.
Sarcomas
(1%) - derived from connective tissue or mesenchymal cells (e.g., bone, fat, cartilage); Karposi’s sarcoma of the mouth, oral and maxillofacial sarcomas are rare
What are the most common tumor sites?
Skin, intestinal epithelial cells, glands
*Tumors generally arise in tissues with actively dividing cells
oral cancer facts
- 1 american dies every hour from some form of oral cancer
- 75% of oral cancer is related to lifestyle choices
- 90% of oral cancers are squamous cell carcinomas
- oral cancers have increased over a 6 year period, while other cancers have decreased
HPV+ squamous carcinoma
Examples of cancers in the oral cavity
common
Malignant melanoma
Examples of cancers in the oral cavity
rare
causes of Conversion to Cancer-associated Genes
- Exposure to carcinogens (certain chemicals, radiation, etc)
- Mistakes in normal cell machinery - e.g., DNA repair defect
- Viral incorporation into genome (e.g., HPV)
Risk factors for oral squamous cell carcinoma
tobacco usage, alcohol consumption, poor oral hygiene, HPV infection
what are the Primary Roles of the Immune System in the Prevention of Cancer?
- Prevents the development of virally-induced tumors by eliminating or controlling viral infections
- Prevents the development of chronic inflammatory environments that are conducive to tumorigenesis by effective elimination of pathogens and resolution of inflammation
- Eliminates tumor cells directly - Immune Surveillance Theory
oncogenic virus
Virus that directly causes cancer: integrates into the genome of the host cell and elicits a response (oncogenes)
Some viruses encode proteins ____ that can directly induce tumor development.
oncogenes
*integrates into host cell and directs tumor development
Human papillomavirus (HPV)
can cause cervical carcinoma, and oral and oropharyngeal cancers
*two decades ago, 20% of oral cancers were HPV-related. Today that number has grown to 50%
Human T-lymphotropic virus (HTLV-1)
one of the few retroviruses (RNA) associated with human cancer; can cause adult T cell leukemia/lymphoma (ATLL; CD4 cell)
Epstein Barr Virus (EBV)
first cancer-causing virus identified; can cause Burkitt’s lymphoma (Central Africa), nasopharyngeal carcinoma (China), B cell lymphoma (major cause in immunodeficient/suppressed patients)
Human herpes virus 8 (HHV8)
can cause Karposi’s sarcoma (associated with AIDS, immunodeficient/suppressed patients; also Africa) in skin and oral cavity
How can chronic unresolved inflammation can promote tumor development?
- Chronic inflammation can result from an ineffective immune response that is unable to eliminate pathogens or (inflammatory) diseases (autoimmune disease with chronic inflammation e.g., SLE & RA with B cell lymphomas; IBD with colon cancer) that are not associated with obvious infection
- not exactly sure why this is
Examples of infectious microorganisms associated with cancer that do not encode oncogene proteins: (do not directly incorporate into host genome and direct tumor growth)
- uncontrolled Helicobacter pylori infection can lead to gastric cancers, MALT lymphomas by causing chronic inflammation
- Hepatitis B & Hepatitis C cause chronic inflammation if not cleared, leading to liver cancer
- Schistosomal infections/tumors of bladder & colon
*infections that become chronic
Immune Surveillance Theory
- immune system identifies and eliminates early stage cancer before it has the chance to grow
- Originally proposed in the 1950s.
- Seems logical, but this hypothesis has been highly controversial
Evidence Against Immune Surveillance
- Cancer is still one of the leading causes of death, suggesting that the anti-tumor response is ineffective
- Immunocompromised (T and B lymphocyte-deficient) mice and patients do not have greater incidence of non-virally associated tumors - would think would have more cancer
What is the exception to the fact that immunocompromised patients do not have a greater incidence of non-virally associated tumors?
Immunosuppressed patients (i.e., kidney transplant patients) - increase in tumors due mostly to tumors associated with virus, (e.g., Kaposi’s sarcoma, non-Hodgkin lymphoma, cervical carcinoma) suggesting immune surveillance may be directed toward virus not tumors
Evidence in Support of Immune Surveillance Theory
- Postmortem data suggest that there are more tumors than are clinically apparent (suggesting that something is controlling them)
- Tumors contain mononuclear cell infiltrates (T cells, natural killer (NK) cells, macrophages); presence of lymphocytic infiltrates in some types of melanoma and breast cancer predictive of better prognosis (the more immune cells present, the better the prognosis)
- Although rare, spontaneous regression of tumors occurs (something must be controlling this)
- Tumors occur more frequently in young children and elderly, i.e., stages of life when immune function is not optimal
- Tumor-specific cytotoxic T cells can be found in circulation of cancer patients
- Tumor immunity can be generated in animal models
Definitive “New” Evidence in Support of Immune Surveillance
- Rag/IFNγ knock-out mice (mice without functional T, B and NK cells) spontaneously develop (non-virally induced) tumors and are much more susceptible to carcinogen-induced tumors: redundancy in immune response
- This is supported by the finding that there is a higher incidence of cancer in immunodeficient/ immuno-compromised individuals (if deficient for both lymphocytes and IFNγ)
Immune responses frequently fail to prevent growth of tumors because:
- Tumors are derived from host cells and are, therefore, weakly immunogenic (we have many mechanisms to prevent autoimmunity)
- Rapid growth and spread of tumors may overwhelm capacity to eradicate tumor cells
- Many tumors have specialized mechanisms for evading host immune responses
It may be possible to generate an effective immune responses against tumors because:
- Tumors do express antigens that can be recognized by the immune system of the host (mutations in proteins)
- Immune system can be stimulated to effectively kill tumor cells and eradicate tumors in animal models
Immune Response to Tumors: Tumor-specific cytotoxic CD8 T cells
- Principal mechanism of tumor immunity
- Peripheral blood lymphocytes, tumor-infiltrating lymphocytes (TIL), and lymphocytes from the draining lymph nodes
- Induction requires cross-presentation by DC, and frequently requires CD4 T cell help
Immune Response to Tumors: Tumor-specific CD4 T cells
- Provide cytokine-mediated help to cytotoxic CD8 cells by providing IL-2 and other cytokines
- Produce TNF and IFNγ - increases Class I expression and increased sensitivity to lysis in tumor cells, activates macrophages
Immune Response to Tumors: Tumor-specific antibodies
- found in cancer patients on occasion
- kill via complement activation or ADCC with macrophages or NK cells
- Unclear whether natural humoral immunity effective in vivo
Immune Response to Tumors: NK cells
- Will attack cells with decreased/low class I (CD8 cells require Class I expression, but NK cells do not)
- Some tumors express NK-activating molecules
- Tumoricidal capacity is increased by IFNγ, IL-15, IL-12.§ - NK deficiency results in increases in certain types of cancer
Immune Response to Tumors: Classically activated (M1) macrophages
- not antigen specific
- Clustered around some tumors and associated with tumor regression
- Activated by tumor cells by unknown mechanism
- Kill tumor cells more effectively than normal cells
- Produce lysosomal enzymes, reactive oxygen species, N intermediates, TNFα
- Alternatively activated (M2) macrophages can also be induced by tumor cells, but can actually enhance tumor progression
How do tumors evade the immune system?
- Some types of tumors lack distinctive antigenic peptides
- Tumor cells are poor antigen presenting cells
- Tumors may induce/expand/attract inhibitory immune cells
- Tumors can secrete or express immunosuppressive factors
- Tumors can impair or inhibit NK cell activity
- Tumor-specific blocking antibodies
- Tumors express high levels of glycocalyx molecules (e.g., mucopolysaccharides) that can hide surface antigens
Why are tumors poor antigen presenting cells?
- exhibit reduced immunogenicity via immunoediting
- lack adhesion molecules that are required for effective tumor cell killing
- do not express either co-stimulatory (e.g., B7) or MHC Class II molecules
How do tumors exhibit reduced immunogenicity via immunoediting?
- can lose antigens spontaneously (shedding) or as result of elimination of high antigen-expressing tumor cells by the immune response (antigen loss variants)
- can lose MHC Class I molecules either through decreased synthesis or selection by the immune response or altered antigen processing machinery (means no longer susceptible to CD8 cells)
Describe how tumors may induce/expand/attract inhibitory immune cells:
- regulatory T cells (normal job is to protect against autoimmunity), but here they inhibit immune system against tumors
- alternatively activated (M2 macrophages) induced: anti-inflammatory; shuts down immune response
- myeloid-derived suppressor macrophages (MDSCs)
Immunosuppressive factors that tumors secrete
- Cytokines or other factors (TGFb, IL-10, IDO)
- apoptosis-inducing factors (FasL that kills cells expressing Fas, like a lot of the T cells)
- inhibitory factors like PD-L1; CTLA-4 may also be involved (but most likely via T cell-APC interaction, not expressed by tumor cells): very strong inhibitors of the immune response
describe the tumor-specific blocking antibodies of tumors
- instead of being antibodies that attack a tumor cell, they prevent the attack/block antigens on the surface
- may bind to antigen on tumor surface and mask antigen from CTL
Monoclonal Antibodies
- Act by either immune-mediated mechanisms (e.g., direct elimination of tumor cells) or through interference with tumor growth (e.g., blocking growth factors)
- Mechanisms of anti-tumor activity: steric inhibition and neutralization, complement activation, and activation of cell- mediated cytotoxicity
- Radioactive isotopes or toxic chemicals (e.g., ricin, diptheria toxin) can also be conjugated to monoclonal antibodies to deliver cytotoxic therapy directly to tumors
- synthesized by pharmaceutical companies
HER2/neu
- growth factor gene highly activated in cells of certain types of breast cancer
- antibody for this works by starving the tumor (against the epidermal growth factor receptor)
- can also induce ADCC (thus directly killing tumor)
Immune Adjuvants
- you can non-specifically inject an adjuvant (Substance that increases the immune response to antigens)
- Bacilli Calmette-Guerin (BCG) injection into bladder wall after resection of tumor - more effective than chemotherapy (approved 1976)
- Toll-like receptor 7 (TLR7) agonist, imiquimod - effective against HPV-induced warts, and low- grade epithelial tumors and precancerous lesions, and more recently, vulvar intraepithelial neoplasia
Cytokine Therapy
- Interleukin-2 (IL-2; approved 1983) and interferon α (IFNα) delivered systemically; response rates low, can be quite toxic
- Tumor necrosis Factor (TNF) delivered locally because highly toxic; quite effective in conjunction with other therapies
Prophylactic Immune Therapy
- Vaccines against oncogenic (e.g., HPV; approved in 2009) and non-oncogenic (e.g., HBV) microorganisms
- Antibiotic treatment to eliminate cancer-causing microorganisms before cancer develops (e.g., H. pylori for stomach cancer) or during early cancer development (e.g., H. pylori for MALT lymphomas)
Bone Marrow Transplantation
Bone marrow ablative therapy (e.g., radiation)
followed by allogeneic bone marrow
transplantation
* graft-vs-leukemia response effective
* severity of graft-vs-host response is inversely
correlated with the risk of relapse
- very dangerous but does work against some leukemias
mechanisms behind eliciting an anti-tumor response
- antibody agonists that can elicit a co-stimulatory response and activate B and T cells
- vaccines: tumor antigen mixed with adjuvants to become an antigen-specific vaccine
- patient’s own DC can be cultured with specific tumor antigen and inject them back into patient (eliciting a CD8 response)
- take tumor cells out of a patient and transfect them: force them to produce a variety of pro-inflammatory cytokines that can help immune system elicit a response against a tumor
- immunization with engineered viruses that have mechanisms to destroy the tumor
Provenge
- First FDA approved therapeutic vaccine for cancer (prostate)
- APCs taken from the patient and cultured with fusion protein (PAP-GM-CSF) to activate the DC with ability to present the particular antigen to CD8 cells
- cells transferred back into patient to get CD8 response
Adoptive Cellular Therapy
The transfer of cultured autologous lymphocytes that have antitumor activity into a patient
- isolate lymphocytes from blood or tumor infiltrate
- expand lymphocytes by culture in IL-2
- transfer lymphocytes into patient, with or without systemic IL-2
- tumor regression
Immunotherapies to treat tumors have not been as effective as we would expect them to be, why?
Negative regulators of the immune response interfere with the induction of tumor immunity
Negative Regulators of the Immune Response
Normally designed to prevent autoimmunity: in this case they prevent our response to tumor cells.
* Populations of lymphocytes that naturally regulate
autoreactive T cells and prevent autoimmune disease
in normal individuals: CD4+CD25+ regulatory T cells
* Inhibitory molecules that downregulate T cells: CTLA-4 and PD-1
CD4+CD25+ regulatory T cells
- Naturally-occurring population of regulatory T cells found in the
periphery in both mice and humans. - 1-5% of circulating CD4+ T cells in humans.
- Very important for the control of autoimmune disease
- Studies suggest that these cells may actually interfere or inhibit anti-tumor T cell responses
- high percentage of these found in late stage ovarian cancer; high numbers of these cells predict poor patient survival
How are CD4+CD25+ regulatory T cells important for the control of autoimmune disease?
- Some autoimmune diseases, including Type 1 diabetes, Multiple
Sclerosis, Systemic Lupus Erythematosus in mice and humans are associated with a deficiency of these cells. - Patients with IPEX, multi-organ autoimmune disease syndrome, have a mutation that prevents development of CD4+CD25+regulatory T cells
“New” strategies for tumor immunotherapy include controlling negative regulators
- Inhibition of natural regulation in conjunction with other therapies:
- Downregulation or elimination of regulatory T cells (e.g., CD4+CD25+ T cells)
- Inhibition of negative signaling (e.g., CTLA-4, PD-1)
Downregulation or elimination of regulatory T cells for controlling negative regulators
Denileukin diftitox (Ontak) - conjugate of diphtheria toxin and IL-2 - currently in clinical trials for treatment of melanoma
Inhibition of negative signaling for controlling negative regulators
- Anti-CTLA-4 blocking antibody enhances T cell activation by
either blocking inhibition of activated effector T cells; may
also block function of regulatory T cells. - Anti-PD-1 or anti-PD1L blocking antibody enhances T cell activation.
Ipilimumab
- blocks negative signaling from CTLA-4
- under normal circumstances, T cell is activated with co-stimulation via CD28. If T cell starts expressing CTLA-4 (happens at end of an immune response to prevent autoimmunity) binds to B7 and is shut down)
- antibody blocking CTLA-4 from binding (antagonist) to B7, then T cell is very activated and can treat tumor cells
Nivolumab
- blocks negative signaling from PD-1
- under normal circumstances, as tumors progress they start expressing PD-L1 (inhibitory molecule for CD8 cells, making them unable to kill tumor cells
- antibody blocks PD-1 or PD-L1 makes CD8 cells capable of killing because negative signaling is removed
