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Micro and Immuno > Cancer Immunology > Flashcards

Cancer Immunology Flashcards

1
Q

Cancer cells have defects…

A

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.

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2
Q

What are the Malignant Tumor Classifications?

A
  • carcinoma
  • leukemias and lymphomas
  • sarcomas
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3
Q

carcinoma

A

(>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

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4
Q

Leukemias and lymphomas

A

(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.

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5
Q

Sarcomas

A

(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

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6
Q

What are the most common tumor sites?

A

Skin, intestinal epithelial cells, glands

*Tumors generally arise in tissues with actively dividing cells

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7
Q

oral cancer facts

A
  • 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
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8
Q

HPV+ squamous carcinoma

A

Examples of cancers in the oral cavity
common

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9
Q

Malignant melanoma

A

Examples of cancers in the oral cavity
rare

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10
Q

causes of Conversion to Cancer-associated Genes

A
  • Exposure to carcinogens (certain chemicals, radiation, etc)
  • Mistakes in normal cell machinery - e.g., DNA repair defect
  • Viral incorporation into genome (e.g., HPV)
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11
Q

Risk factors for oral squamous cell carcinoma

A

tobacco usage, alcohol consumption, poor oral hygiene, HPV infection

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12
Q

what are the Primary Roles of the Immune System in the Prevention of Cancer?

A
  • 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
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13
Q

oncogenic virus

A

Virus that directly causes cancer: integrates into the genome of the host cell and elicits a response (oncogenes)

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14
Q

Some viruses encode proteins ____ that can directly induce tumor development.

A

oncogenes

*integrates into host cell and directs tumor development

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15
Q

Human papillomavirus (HPV)

A

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%

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16
Q

Human T-lymphotropic virus (HTLV-1)

A

one of the few retroviruses (RNA) associated with human cancer; can cause adult T cell leukemia/lymphoma (ATLL; CD4 cell)

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17
Q

Epstein Barr Virus (EBV)

A

first cancer-causing virus identified; can cause Burkitt’s lymphoma (Central Africa), nasopharyngeal carcinoma (China), B cell lymphoma (major cause in immunodeficient/suppressed patients)

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18
Q

Human herpes virus 8 (HHV8)

A

can cause Karposi’s sarcoma (associated with AIDS, immunodeficient/suppressed patients; also Africa) in skin and oral cavity

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19
Q

How can chronic unresolved inflammation can promote tumor development?

A
  • 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
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20
Q

Examples of infectious microorganisms associated with cancer that do not encode oncogene proteins: (do not directly incorporate into host genome and direct tumor growth)

A
  • 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

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21
Q

Immune Surveillance Theory

A
  • 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
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22
Q

Evidence Against Immune Surveillance

A
  • 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
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23
Q

What is the exception to the fact that immunocompromised patients do not have a greater incidence of non-virally associated tumors?

A

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

24
Q

Evidence in Support of Immune Surveillance Theory

A
  • 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
25
Q

Definitive “New” Evidence in Support of Immune Surveillance

A
  • 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)
26
Q

Immune responses frequently fail to prevent growth of tumors because:

A
  • 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
27
Q

It may be possible to generate an effective immune responses against tumors because:

A
  • 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
28
Q

Immune Response to Tumors: Tumor-specific cytotoxic CD8 T cells

A
  • 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
29
Q

Immune Response to Tumors: Tumor-specific CD4 T cells

A
  • 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
30
Q

Immune Response to Tumors: Tumor-specific antibodies

A
  • 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
31
Q

Immune Response to Tumors: NK cells

A
  • 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
32
Q

Immune Response to Tumors: Classically activated (M1) macrophages

A
  • 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
33
Q

How do tumors evade the immune system?

A
  • 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
34
Q

Why are tumors poor antigen presenting cells?

A
  • 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
35
Q

How do tumors exhibit reduced immunogenicity via immunoediting?

A
  • 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)
36
Q

Describe how tumors may induce/expand/attract inhibitory immune cells:

A
  • 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)
37
Q

Immunosuppressive factors that tumors secrete

A
  • 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
38
Q

describe the tumor-specific blocking antibodies of tumors

A
  • 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
39
Q

Monoclonal Antibodies

A
  • 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
40
Q

HER2/neu

A
  • 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)
41
Q

Immune Adjuvants

A
  • 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
42
Q

Cytokine Therapy

A
  • 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
43
Q

Prophylactic Immune Therapy

A
  • 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)
44
Q

Bone Marrow Transplantation

A

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

45
Q

mechanisms behind eliciting an anti-tumor response

A
  • 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
46
Q

Provenge

A
  • 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
47
Q

Adoptive Cellular Therapy

A

The transfer of cultured autologous lymphocytes that have antitumor activity into a patient

  1. isolate lymphocytes from blood or tumor infiltrate
  2. expand lymphocytes by culture in IL-2
  3. transfer lymphocytes into patient, with or without systemic IL-2
  4. tumor regression
48
Q

Immunotherapies to treat tumors have not been as effective as we would expect them to be, why?

A

Negative regulators of the immune response interfere with the induction of tumor immunity

49
Q

Negative Regulators of the Immune Response

A

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

50
Q

CD4+CD25+ regulatory T cells

A
  • 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
51
Q

How are CD4+CD25+ regulatory T cells important for the control of autoimmune disease?

A
  • 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
52
Q

“New” strategies for tumor immunotherapy include controlling negative regulators

A
  • 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)
53
Q

Downregulation or elimination of regulatory T cells for controlling negative regulators

A

Denileukin diftitox (Ontak) - conjugate of diphtheria toxin and IL-2 - currently in clinical trials for treatment of melanoma

54
Q

Inhibition of negative signaling for controlling negative regulators

A
  • 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.
55
Q

Ipilimumab

A
  • 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
56
Q

Nivolumab

A
  • 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

Micro and Immuno (17 decks)

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