Question

It was all over the news this morning (March 29, 2018) that a new cancer “vaccine” was about to begin human trials after a 97% success rate in mouse trials against both blood cancers (lymphomas) and solid tumors such as breast and colon cancer. I will excerpt a description compiled from several scientific and news sources. Based on what we talked about in Bio 221, you should be able to understand this. Answer each of the questions about this exciting new “vaccine.”

T cells are present in most tumors by infiltration. These include CTLA4-expressing Treg cells, as well as CD4- expressing TH cells and CD8-expressing cytotoxic T-lymphocytes. Once cancer is well established, the balance between these inputs is tipped toward immunosuppression. We found that a Toll-like receptor 9 (TLR9) ligand, CpG, induces the expression of OX40, an alternate costimulatory receptor, on CD4 T cells when it is injected into the tumor microenvironment. This is an indirect induction, in which CpG induces cytokine secretion by myeloid cells which in turn induces OX40 expression on T cells. Then OX40 can be activated using anti-OX40 antibodies, thereby activating TH cells in the tumor.

A. What is CTLA4 and how does it establish immunosuppression?

B. What is a costimulatory receptor, and why is an alternate one required here?

C. How does a TLR ligand such as CpG induce cytokine expression by myeloid cells? What myeloid cells are involved here?

D. How do antibodies that recognize OX40 help to stimulate TH cells? (Hint: think about autoimmune diseases. There is one we didn’t talk about, called Graves’ disease, that you might want to look up, too.) What else is required for the TH cells to become activated? E. How does all of this kill the cancer cells? What other cells in the tumor also must become activated? How? F. How does this differ from the CAR-T cell therapy?

Answer 1

1.

• CTLA4 - Cytotoxic T lymphocyte associated antigen 4 is CTLA4 . It is immunosuppressive and reduces the effects of T cells.
• It is type of CD28.
• C28 ligation is necessary for optimal action of T cells. But binding of CTL4 causes T cell to unable to exert its complete effects. It inhibits interleukin 2 and cell cycle progression .
• This causes immunosuppression .

2.

• Costimulatory receptor are receptors activated inorder to optimise the T cell response.
• But here CTL4 creates immunosuppression but decreasing the effects of T cells and hence alternate is required.

3.

• By activation of mitogen activated protein kinases, Nuclear factor kappa activation leads to production of cytokines.
• Here it must be monocytes derived myeloid cells.

4.

• Decresaes the expression and devlopment of tumor cells .
• It induces production of CD8 cells and helper T cells.