immunology: class notes 3/8/9- cancer

this lecture focused on cancer from an immunological perspective. tumors appear in the body on a somewhat regular basis due to viral infection. because these tumors are virally induced, the APC's that bind to tumor cells will also express co-stimulatory molecules (viral elements will bind to toll like receptors). however, in cancerous tumors, this is not necessarily the case, and tumors can subvert the surveillance of the immune system by the absence of these co-stimulatory molecules. in this case, macrophages can go so far as to eat the dead tumor cells (cells on the center of the tumor die because of the lack of blood supply) and present them in MHC class II; but since there is no CD86, an immune response will not be mounted.

there are several approaches to cancer treatment. first is a historical approach with "coley's toxin", which is basically ground up, heat killed gram negative bacteria that is injected at the tumor site. the bacteria signals an infection and the APC's that are presenting the tumor peptide are able to express the co-stimulatory molecules required to mount an immune response (note- this method also induces a high fever in its patients). a more modern approach is the dendritic cell treatment, which isolates dendritic cells outside of the body, stimulates them to differentiate with GMCSF and IL-4, exposes them to heat killed tumor, and injects them back into the body to mount an immune response. this method is effective but as it is completely individualized, is prohibitively expensive and hard to access.

some ways that the presence of a tumor can be identified: the abnormal or over expression of proteins, high telomerase activity (telomerase is an enzyme that adds base pairs to the end telomeres of genes during DNA replication), and other tumor specific antigens. some of these include MAGE and MART in melanoma, BRCA 1-5, MUC 1-3 in breast cancer, prostate specific antigen in prostate cancer.

questions
treatment strategies...
1. describe the studies performed in mice that lead to the conclusion that injecting dead tumors can confer protectivity.
2. how does protectivity of the dead tumor cells depend on the method used to kill the tumor?
3. how are non-cancerous tumors normally destroyed by the body?
4. what is the idea behind IL-2 treatment and what are its pitfalls?
5. what is the dendritic cell cancer treatment and what are its pitfalls?
6. what is "coley's toxin"?

tumor specific antigens...
7. what is the relationship of tumors and telomeres?
8. what is the problem with mounting an immune response against cells with high levels of telomerase?
9. what are three ways that protein expression can indicate presence of tumors?
10. what are the tumor specific antigens in melanoma?
11. what are the tumor specific antigens in breast cancer?
12. what are the tumor specific antigens in prostate cancer?
13. how do most tumors escape immunosurveillance?

14. what are the different ways that cells of the immune system could potentially kill tumor cells?
15. what is the relationship between severe burns and cancer treatment?

answers
1. in one study, two mice were injected with dead tumor A, and then one mouse with live tumor A and the other with live tumor B. the mouse injected with tumor A survived and the other died. in another study, two mice were injected with dead tumor A, then had their t cells depleted. one mouse was then injected with tumor A and the other with tumor B; both of them died. these studies showed that injecting a dead tumor can confer protectivity against its live counterpart as long as t cells are in healthy supply.
2. the tumor cells must be killed via necrotic cell death (generally by freeze-thawing twice)- necrosis causes CD86 expression which mimics infection and can provoke an immune response.
3. most of these tumors are virally caused and therefore express CD86; the immune system can mount a response to them immediately.
4. IL-2 is the cytokine involved in t cell proliferation and thus might be able to intensify the t cell population's response to the tumor. however, it can cause t cells not specific for the tumor to divide, and also cause systemic shock simply because of the presence of high cytokines levels in the blood.
5. similar to the HIV DC treatment; removing DC cells, putting them in a dish with GMCSF and IL-4 to induce differentiation, then adding necrotically killed tumor cells- this causes DC's to secrete IL-12, CD86. DC's are them put back into the host and migrate to the lymph nodes where they mount an immune response agains the live tumor; the downside is that this is a completely individualized treatment and prohibitively expensive. also, treatment depends on the individual having a functioning immune system and thus chemotherapy patients must wait 2-6 years before receiving the treatment.
6. ground up, heat killed, gram negative bacteria that is injected in cancer patients at tumor sites; binds to TLR's and induces expression of co-stimulatory molecules so that CD8 t cells can be activated. treatment also causes high fever.

7. most tumor cells have overactive telomerase activity, which normally add base pairs to the end of genes during DNA replication.
8. stem cells also have high levels of telomerase.
9. presence of mutant proteins, abnormal expression of protein (foot protein being expressed in head), over-expression of proteins.
10. MAGE, MART
11. BRCA 1-5, MUC-1,3
12. prostate specific antigen
13. the absence of CD86 expression, the fact that the cells originate from the self, the expression of low levels of MHC (sometimes the tumor cells make their own MHC molecules), and cytokine production such as TGF-beta which can inhibit t cell activity.

14. CD8 t cell mediated immunity, macrophage production of reactive oxygen species, NK cell response (?).
15. burn victims express high levels of TNF-alpha, which aids in the protection against cancer.