Mkgrady8 Host 4 Cancer And Its Interactions With The Immune System

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how can a tumor evade the immune system

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it can loose the antigen that alerted the immune system (antigen loss variants), it can loose the antigen processing molecules (MHC molecules on the surface), it can down regulate the MHC, is can secrete immunosuppressive proteins, it can express Fas L, it can induce Tregs, it can induce myeoloid derived suppressor cells (MDSC); this is all just like what a bac or virus would do to evade

Front 2

Mage-1 or MART-1

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among the first human tumor antigens cloned; stands for melanoma antigen 1 or melanoma antigen recognized by T cells 1

Front 3

the major thing that is recognized in these tumor cells

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over expressed normal self genes making too many normal self peptides

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TAA (tumor associated antigens) ID methods

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cDNA libraries (requires specific T cells); SEREX (serological analysis of recombinant cDNA expression libraries) (requires specific antibodies); 2D-PAGE/mass spec (proteomics) (requires specific antibodies); reverse immunology= subtraction hybridization, phage display libraries, peptide elution form MHC class I, serial analysis of gene expression (SAGE), differential display RT-PCR

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immune responses against tumors

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T cells are the primary effectors against solid tumors; NK and NK-T cells may be important for killing MHC class-I negative tumors; an active role for B cells or antibodies has been demonstrated (passive administration of specific mAb) used to treat some cancers; immune checkpoint blockade); an active role for macrophages has been demonstrated

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induction of T cell responses to tumors

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induction of CTLs usually requires cross priming of T cells by DCs; most tumors lack co stimulatory molecules, an exception is B cell lymphoma; cross priming is the basis for ex vivo DC based tumor vaccines; T cell responses can be induced via vaccination using TAA so antigens are cross presented

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a role of NK cells

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MHC-I is inhibitory to NK cells; so MHC-I negative tumors may then be susceptible to NK cell killing (why would they try to get rid of their MHC-I? to evade the CD8 T cells

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categories of tumor immunotherapy

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passive (short term therapy that has a half life)= administration of monoclonal antibody (FDA approved therapy), systemic cytokines, adoptive cell therapy (ACT)(T cell transfer); active (confers immunity for a lifetime)= vaccines (represent the majority of clinical trials several near FDA approval, one approved 2010)

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CTLA-4 and PD-1 checkpoint blockade to induce effector T cell function

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you give the pt antibodies against CTLA-4 and PD1 so that they are blocked and the T cell always becomes effector and does its thing (CTLA-4 and PD-1 (co inhibitory signals) usually used to stop the cell from reacting to self cells); checkpoint blocking allows a sustained T cell response to include an increase in inflammatory and effector cytokine production

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adoptive cell therapy (ACT)

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grab T cells from a pt with cancer, test them to find some that attack the cancer cells (in culture) then proliferate them and give them back to the pt; can take this a step further and destroy all their other T cells (lymphodepletion) so that you can pump them pull of these specific T cells

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chimeric antigen receptor T cells

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modify the T cell so that it expresses a specific receptor so that they T cell doesn't have to be from that pt; so basically taking T cells and putting your own lab constructed receptors on them against the cell causing cancer so that when they see them they kill them; a type of ACT; need to make sure they can be killed when they are done

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systemic cytokine therapy

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give the pt IL-2, IF-alpha, IL-12 etc; this can be highly toxic to the pt

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prophylactic cancer vaccine

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like gardasil; it's a human papilloma virus vaccine; stops cervical cancer

Front 14

how sipuleucel-T works

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monocytes isolated from a prostate cancer pt are cultured with a fusion protein of GM-CSF and prostatic acid phosphatase (PAP) --> GM-CSF induces the monocytes to mature into DCs and PAP is internalized with the GM-CSF and is processed into peptides that are presented by MHC class II --> the activated DCs are infused into the pt where they travel to the spleen and present PAP antigens to naive T cells

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tumor vaccine approaches

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purified tumor antigens (peptides); professional APC based vaccines (DC based); cytokine and costimulator enhanced vaccines (gene modified whole tumor cells- make tumor cells make a bunch of Bt, IL-2, and GM-CSF all the time to get activation of a bunch of tumor specific T cells); DNA vaccines (plasmid DNA based)