immune response to tumors

Question 1

define tumor/neoplasm

Answer 1

abnormal tissue growth resulting from cells that have abnormally proliferated

Question 2

define metastatic

Answer 2

Tumor cell clusters that migrate from the point of origin to other sites of the body

Question 3

linked etiology of cancer in humans

Answer 3

genetic inheritance, age, hormones, lifestyle (i.e. smoking, drinking, drug usage, obesity), exposure to the sun, select viral exposure (i.e. Epstein-Bar or Human Papilloma virus), chemical toxin exposure or excessive exposure to radiation

Question 4

tumor antigens

Answer 4

cancer cells can display novel proteins that are foreign to the immune system resulting in an immune response

Question 5

mutated gene p53

Answer 5

• cell proliferation suppressor protein
• Mutation in the genes that code for p53
  leads to a conformational change in this protein in loss of the suppressor function of this protein resulting in uncontrolled proliferation
• any human and animal cancers are linked to
  this mutated protein

Question 6

mutation gene cyclin-dependent kinase-4 (CDK-4)

Answer 6

conformational change in this enzyme reduces binding affinity to the protein p16INK-4, which is a tumor suppressor protein

Question 7

oncofetal tumor antigens

Answer 7

tumor antigens that are typically expressed by “normal” cells only during embryogenesis during pregnancy. When these tumor antigens are expressed in the host outside of pregnancy, they too are viewed as foreign by the host and generate an immune response.

Question 8

examples of oncofetal tumor antigens

Answer 8

α-fetoprotein (AFP), carcinoembryonic antigen (CEA) and melanoma-associated antigen (MAGE)

Question 9

examples of differentiation leading to
the upregulation of tumor antigens that are products of normal genes that over-express certain proteins that become tumor antigens.

Answer 9

prostate-specific antigen (PSA), tyrosinase in melanoma and HER-2/neu in breast and ovarian cancer. Clonal amplification of neoplastic B cells with same idiotype in lymphoma also falls within this classification

Question 10

oncogenes

Answer 10

• genes in the genome that are usually silent, but when activated can cause cancer
• mammals
• triggered by point mutations,
  gene amplification, chromosome rearrangement and viruses. Many of the above examples fit this classification

Question 11

mechanism of oncoviruses

Answer 11

upon infection, insert either their DNA or RNA into the host cell causing the cells to clonal proliferate

Question 12

Epstein-Barr virus (EBV)

Answer 12

herpes virus transmitted via the saliva. It is associated with Burkitt lymphoma, certain types of Hodgkin’s and non-Hodgkin lymphoma and stomach cancer as well as a number of other non-cancerous diseases (i.e. multiple sclerosis). Currently, no vaccine has been developed against this virus. The two reasons provided is that the virus is exceptionally good at hiding and there is concern that a vaccine might precipitate cancer formation

Question 13

Hepatitis B virus (HBV)

Answer 13

double-stranded DNA orthohepadnavirus spread by body fluids. It is the most common cause of liver cancer. There is a vaccine for this virus and is routinely administered to children and adults

Question 14

Hepatitis C virus (HCV)

Answer 14

enveloped single strand RNA flavivirus spread via infected
blood. It is also a leading cause of liver cancer and has been reported to cause non-
Hodgkin’s lymphoma if not treated. This virus is treatable.

Question 15

Human Herpesvirus-8 (HHV-8)

Answer 15

spread via saliva, but also
through other body fluids (i.e. blood, semen and vaginal fluids). It is rare in the US
between 1-5% of the population. It typically is associated with Kaposi sarcoma in
individuals with weakened immune systems, such as patients with HIV

Question 16

Human papilloma virus (HPV)

Answer 16

papilloma virus, of which there are 12 strains, is the
most common sexually transmitted virus that can cause anal, liver, lung, throat, vaginal
and vulvar cancer. Currently, there are 3 vaccines targeting HPV strain 16 and 18. The
vaccine, Gardasil, prevents strains 6 and 11, which are associated with 90% of genital
warts. Vaccines are typically administered to teens and young adults

Question 17

Human T-cell lymphotropic virus-1 (HTLV-1)

Answer 17

RNA retrovirus that is spread by
blood transfusions, semen, vaginal fluids and breast milk. It is associated with adult T -
cell leukemia/lymphoma. This viral infection is rare in the U.S

Question 18

Merkel Cell Polyomavirus (MCPyV or MCV)

Answer 18

newly discovered double
stranded DNA orthopolyomavirus that causes a rare skin disease called Merkel cell
carcinoma (MCC). It does not seem to be too much of a concern in healthy individuals,
but it is especially deadly to immunocompromised individuals.

Question 19

immunosurveillance

Answer 19

hen cells become neoplastic, they express
proteins that are foreign to the host. This typically results in a host immune response against
the neoplastic cell(s)

Question 20

cancer immunoediting

Answer 20

3 phases that can occur after the cell becomes neoplastic. In all 3
phases, the immune system is active and targeting the cancel cells for removal, usually by
apoptosis.

Question 21

elimination

Answer 21

neoplastic cell expresses its foreign tumor antigens and is
attacked by the innate and adaptive cells and immune proteins of the immune system and is
destroyed

Question 22

equilibrium

Answer 22

same process occurs, but not all
the cancer cells are eliminated, and these cells reach a sort of equilibrium.

Question 23

escape

Answer 23

associated with the cancer cells being able to mobilize away from the immune assault

Question 24

macrophages and neutrophils

Answer 24

The general consensus is that direct activation of macrophages
and neutrophils against tumor cells does not occur, unless in the presence of bacteria. Rather, it
is the activated CD4+ T cells that release cytokines (i.e. IFNγ) however, when activated the
macrophages and neutrophils can have potent cytotoxic effects via the release of lysosomal
enzymes and innate cytokines (i.e. TNFα). There are studies that have shown that activated
macrophages do have a critical role during tumor regression. Further, in vitro studies have
shown that, in the presence of antibodies to the tumor cells (anti-serum) and complement, that
phagocytosis is enhanced.

Question 25

B cells and antibodies

Answer 25

since cancer involves cellular changes, it is believed that
humoral immunity has a supportive role in tumor cell removal and destruction. At the tumor
cellular level, IgG or IgM antibodies against tumor antigens + complement can destroy tumor
cells, in vitro. However, other studies with the solid form of the same tumor, have shown
decreased efficacy in tumor destruction. One other study has shown that antibodies that target
cell adhesion proteins on tumors can impair metastasis. Finally, antibody bound to tumor-
specific antigens can activate the ADCC involving CTLs and NK cells

Question 26

T cells

Answer 26

he CD8+ cytotoxic T cells (CTLs) play a major role in tumor
antigen and viral-infected tumor cell destruction, which also secrete cytokines (i.e.
IFNγ,TNFα). In addition, as mentioned above, CD4+ T cells also play a major role in directing
the CTLs and the innate cells via cytokine secretion (i.e. IFNγ)

Question 27

NK, NK/T, TIL and LAK cells

Answer 27

NK cells, as you may recall, are activated when viral-infected cell
down-regulate MHC I surface molecules. It is believed, but not definitively proven, that NK cells
are similarly activated if tumor cells also block MHC I. Activated NK cells can secreted
TNFα. NK/T cells are also believed to have a similar role. Lymphokine activated killer (LAK)
cells are peripheral blood CTLs harvested from the patient and cultured with the patient’s
tumor cells in the presence of cytokines. They are then adoptively transferred into the patient
in the hopes that it will enhance killing of the tumor cells. It appears to have mixed success.
Another similar approach is harvesting T cells that have infiltrated the tumor and conducting
the same culture conditions as the LAK cells. Apparently, this has had better success in human
patients

Question 28

cytokines

Answer 28

In addition to ramping up activation of the innate and adaptive immune cells, TNFα and IFNγ
can upregulate MHC I and MHC II molecules on tumor cells, which enhances T cell activation
(Figure 2). Other important cytokines include: IL-1, IL-2, IL-17, IL-12 and GM-CSF

Question 29

Tumor cell evasion

Answer 29

This event is mediated primarily either by the tumor cell(s) or by a deficiency
in the host’s immunity
The one thing that we know about tumor cells is that they can alter their genes and thus the
products they produce or not produce. Tumor cells can undergo mutation in their MHC
molecules creating new ones, which affects or delays host immune response. They can alter or
inhibit tumor antigen binding to MHC. They alter or inhibit synthesis of the tumor antigens
driving the immune response sometimes called antigen loss variants. Tumor cells can actually
secrete immunosuppressive cytokines like TGFβ. They can also express apoptosis-inducing
ligands such as FasL. They can promote upregulation in host T-reg cells resulting in immune
tolerance to the tumor cells. Some tumor cells can also secrete a glycocalyx rich in sialic acid-
containing mucopolysaccharides that coat the tumor cell making it invisible to the immune cells
known as antigen masking. Another obvious factor that make some individuals more
susceptible to tumor formation would be the immune status of the host. Individuals who have
compromised immunity due to a previous disease (i.e. AIDS) are much more susceptible to
tumors

Question 30

Tumor Immunodiagnostics

Answer 30

Some tumors can produce select proteins that can be measured in
the serum or plasma of blood. There are 5 clinical examples in humans in your textbook, that I
will briefly highlight. Myeloma cells, which we covered earlier in the lecture of tumors of the
immune system, can produce not a non-functional antibody that can be measure in the serum
(monoclonal gammopathy) and in the urine (Bence Jones Protein) via electrophoresis. Alpha-
fetoprotein (AFP) in high concentrations in young and adult patients has been linked to liver,
testicular and ovarian cancers, but has also been associated with non-cancerous disorders.
Carcinoembryonic antigen (CEA) has been associated with GI tumors, but like AFP other non-
cancerous disorders. Prostate-specific antigen (PSA) is very specific for prostate cancer and is
confirmed via multiple biopsy of the prostate. Cancer antigen-125 (CA-125) is routinely run in
woman suspected of having ovarian cancer, although it can also be elevated in patients with
peritoneal inflammation. I use to run this assay as well as the CEA and AFP assays when I was a
medical technologist many years ago. This may seem obvious, but diagnosis of cancer using
these assays is not made solely on the result of these tests alone