Cancer immunology and immunotherapy

First an aside  Oncogenes and tumor suppressor genes.  Definitions anyone?  Oncogene –  Tumor suppressor gene –  So for each of these – do we need a mutation on one allele or both alleles?  PLx4302 – targets an enzyme in the BRAF pathway potentially causing apoptosis in melanomas.  Imiquimod – Cream – used for some skin cancers. Debate about how this works. Also has bad side effects.

Immunosurveilance  So this is the idea that the as part of its normal function the immune system is also responsible for surveying the body for emerging malignant cells and destroying them.  One of the stronger arguments for this is the high frequency of cancer in immunodeficient patients.

Self and non-self  Our immune system in order to actually kill something needs to be able to recognise it as non-self. So we are going to talk about tumor antigens for a little bit.  There are a number of different ways in which tumor antigens can occur.  Products of mutated genes  Overexpressed or aberrantly expressed cellular proteins  Tumor antigens produced by oncogenic viruses.  Oncofetal antigens  Let’s look at some of them in a bit more detail.

Products of mutated genes  So tumors have genetic alterations in their oncogenes and tumor suppressor genes so these can result in proteins that are recognised as non-self.  Tumors tend to be genetically unstable so you also get these bizzare genes which code for proteins that have no apparent function but which may serve as tumor antigens.  This has been somewhat confirmed by the presence of CD4+ and CD8+ cells in cancer patients that are able to respond to mutated oncogenes such as RAS and p53.  This is kind of exciting as it makes immunisation against some types of cancer a real possibility.

Overexpressed or aberrantly expressed  Tumor antigens may be normal cellular proteins that are abnormally expressed in tumor cells and elicit an immune response.  For example – melanocytes use an enzyme called tyrosiene as part of melanin biosynthesis. Now this is normally produced in such small amounts that it is not recognised by the immune system. An immune response based on this antigen has been observed in the wild.

Effector mechanisms  Ok so we have an antigen. Next we have our effector mechanisms. Do you find it surprising that cell mediated immunity appears to dominate?  Cytotoxic T cells  protective role against virus associated neoplasms  NK cells  Capable of destroying tumor cells without prior sensitisation making them the first line of defence.  Macrophages  T cells, NK cells can make IFN-gamma which activates macrophages.  Antibodies  Not a big thing in the wild, but administration of monoclonal antibodies against tumors has been effective in some cases.

Tumor Escape Mechanisms  Selective outgrowth of antigen negative elements  Loss or reduced expression of MHC molecules.  Lack of costimulation that is required by some effector cells.  Immunosuppression  Release of TGF-beta – immunosuppressant  Engagement of T cell inhibitory receptor CTLA4.  Antigen marking – hiding surface antigens  Apoptosis of cytotoxic t cells – e.g. some melanomas express FasL which results in the ability to kill Fas expressing T lymphocytes.  Many others.  It has also been in observed that the immune system aids in the growth of some tumors. Of interest here is the release of some growth factors, and the role of regulatory T cells.

Immunotherapy  Goal – actively enhance the immune response or passively deliver immune effectors.  Have  Passive immunotherapy – transfer of in vitro cells/antibodies  Adoptive cellular therapy – form of passive immunotherapy involving T cells (more successfully memory cells)  Active immunotherapy – promotes immune responsiveness.  Obvious idea would be the use of cytokines but this appears to have too many side effects. Has had some success with the suppression of immune inhibitors.  Vaccinations  Evidence of T cell priming has been observed in vitro but it has had little clinical effect – still a lot of progress to be made.  One of the successes involves improving the strength of immunogenicity of the tumor antigen.  Some success with a prophylactic vaccine targeting a virus.

FIRST QUESTION TIME  Ok we have tumor cell which is making some weird proteins (non-self) in its cytoplasm. Detail how an immune response could be mounted against this tumor cell. Give as much detail as you can. I may draw on the blackboard as you talk.