It was all over the news this morning (March 29, 2018) that a new cancer “vaccin

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?

Explanation / Answer

A.

CTLA-4 (The cytotoxic T-lymphocyte-associated antigen) is the immune checkpoint and is the negative regulator of the T-cell function. When there is a increased activation of the T cells with the help of costimulatory signal called as CD28 than CTLA-4 help in regulating the whole machinery. CTLA-4 also help in producing the immunosupression. CTLA-4 is a competitor of the costimulatory receptors. The permanent binding of CTLA-4 will not allow the CD28 ligand to bind to the receptor and this will cause the anergy of T cells. The unreactive T cells will not attack the nonself tissue. So, this is how it is helpful in the immunosuppression.

B.

Costimulatory receptor is one that allow the binding of costimulatory ligand like CD28. This help in the providing the signal 2 which is necessary for the activation of T cells. The costimulatory signal is provided by the APCs to T cells for their activation. Normally tumor cells do not allow the activation of T cells by reducing the efficiency of costimulatory receptors. This is the reason that the alternative costimulatory signal is required t activate the T cells within the tumor cells to kill them.

C.

TLR ligand like CpG stimulate the TLR that result in the activation of innate immune cells. The myeloid cells are majorly activated to express the cytokins like IFN-beta. The major myeloid cells that are involved in this are macrophage and dendritic cells.

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