4. It was all over the news this morning (March 29, 2018) that a new cancer \"va
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4. 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 L23 A. What is CTLA4 and how does it establish immunosuppression? L23] B. what is a costimulatory receptor, and why is an alternate one required here? L23, C. How does a TLR ligand such as CpG induce cytokine expression by myeloid cells? What L20 | myeloid cells are involved here? ?23 ?25 D. How do antibodies that recognize OX40 help to stimulate TH cells? (Hint: think about autoimmune diseases from lecture 25. There is one we didn't talk about, called Graves' disease, that you might 'vant to look up, too.) What else is required for the TH cells to become activated? L231 E. How does all of this kill the cancer cells? What other cells in the tumor also must become L24 activated? How? ?24 | F. How does this differ from the CAR-T cell therapy that we talked about in Lecture 24?Explanation / Answer
CTLA-4 is cytotoxic T-lymphocyte–associated antigen 4. More specifically it’s a type I transmembrane T cell inhibitory molecule which is a member of the Ig superfamily.
CTLA-4 is derived from intracellular vesicles to the immunological synapse in beginning 1-2 days after T cell activation is achieved.
It is having a very good immunosupresive action as it has been eshtablished to affect dendritic cell (DC) function through inducing the immunosuppressive indoleamine 2,3 dioxygenase (IDO) pathway.
Costimulatory Molecules are required for the initiation of effector and memory cytotoxic T lymphocytes.
CD28/B7 and HSA provide two alternative costimulatory pathways for induction of immunological memory as they are highly site specific.
TLRs function as co-stimulatory receptors complementing TCR-induced signals to augment effector T cell proliferation, survival as well as cytokine production. These receptors are greatly expressed on myeloid cells of the innate immune system including macrophages and dendritic cells.
Myeloid cells provide cell surface Immunoglobulin domain/site for the triggered receptor response.
It is well reported that the antibodies targeting human OX40 tend to expand the effector T cells and thus they block inducible as well as natural regulatory function of T cell .
In this way by utilizing above mechanism of inducing tumor-specific T cell response cancer vaccines are developed.
CAR-T cell therapy works by engineering patients' Immune cells to treat cancer but here in all cases we are targeting the T-cells by some markers or modulating the effect of the cells.
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