explain cross priming in the context of tumor immunology

tumor cells are not APCs and so cannot activate T cells

priming of CTLs requires presentation of tumor Ag by host APCs like DCs = cross priming

the recognition of tumor Ag allows for full co signals to develop and for a fine tuning of T cell response

• lack of co-stimulation
• exaggerated co-inhibition

both would render T cells unresponsive to Ag and results in tolerance

what are some of the effector mechanisms used by primed T cells on tumor cells?

• cell to cell interaction (ie:  FasL-Fas)
• soluble factors (ie: IFN gamma)
• cytotoxic granules (ie: perforin/granzyme)

how are NK cell recognition and effector functions regulated?

• the "missing self mechanism"
  • cells missing autologous MHC Ag are selectively recognized and preferentially eliminated by NK cells
• since many types of tumor cells downreg the MHC class I to evade tumor specific T cells, missing self recognition by NK cells is an essential complement to T cell mediated tumor immunity

in addition to missing self mechanism, how else do NK cells kill tumor cells?

NK cells interact with tumor cells and eliminate them through Ab-dependent cellular cytotoxicity (ADCC) in the presence of tumor-reactive Abs

what are examples of evidence for immunosurveillance?

• immunodef pts are vulnerable to certain types of cancers, incl lymphoma
• mice def of immune effector molecules freq develop spontaneous tumors
• spontaneous infiltrations of immune cells in tumor site correlate with an improved clinical outcome in certain types of cancer

in the process of anti-tumor immunity, highly immunogenic tumor cells are eliminated by immunosurveillance and those with less immunogenic features escape immunosurveillance and begin to grow as a tumor mass

tend to be genetically and immunologically more aggressive in phenotype compared to immunodeficient mice

1. IGNORANCE: lack of tumor recognition by immune cells due to loss of tumor Ag and/or MHC expression on tumor
2. DELETION: apoptosis of immune cells triggered by tumor-derived pro-apoptotic factors
3. ANERGY: unresponsive state of immune cells due to a lack of co-stimulatory signals
4. SUPPRESSION: passive inhibition of tumor-reactive immune cells by suppressive factors and cells

what are examples of passive tumor immunotherapy?

• adoptive transfer of tumor-reactive immune cells
• Abs reactive with tumor-associated proteins
• systemic administrations of cytokines

• vaccine of DCs expressing tumor Ag
• tumor cells expressing immune stimulators via genetic mods
• mAbs targeting cosignal molecules

what are some of the potential reasons for the better clinical response in patients who have undergone lymphodepletion before adoptive transfer of Ag treated cells?

• depletion of Treg cells
• creation of immunological space of T cell compartment
• enhanced homeostatic prolif of adoptively transferred T cells due to increased availability of cytokines IL7 and IL15

what are examples of oncogene of mutated tumor suppressor gene products that may function as Ags to be recognized by T cells?

oncogene products

• Ras
• Bcr/Abl fusion protein

mutated suppressor gene products

• mutated p53 protein

"normal" Ags present in large amounts because it is produced by cancer cells

present only on cancerous cells and not on any normal cells

APC presents MHC bound peptide to T cell w/o costimulatory signal, resulting in anergy or ignorance

what signals are involved in fine tuning T cell response to Ag?

• Ag
• co stimulator
• co inhibitor

the balance of co stimulatory and co inhibitory signals creates T cell response

what positive co-signals do APCs have on their surface?

B7 (CD80, CD86): is a ligand that binds CD28 on T cell

CD40: is a receptor that binds CD40L on T cell

what is the effector mechanism of CTL tumor killing?

• Fas (on surface of infected cell)/FasL (on CTL)
  • cell to cell contact
• perforin/granzyme
  • soluble factors/cytotoxic granules

both mechanisms result in apoptosis

how do immune cells recognize tumor that is missing MHC?

• IgG Ab coats cell via binding to surface Ag
• IgG Ab (Fc-gamma) binds to FcgammaIII low affinity receptor on NK surface
• this Ab binding to low affinity Fc receptor stimulates NK killing of the Ab-coated cell

this process is called ADCC: Ab opsonization aids NK response as it interacts with Fc gamma Rs on NK cell

ignorance = lack of tumor recognition by immune cells

• loss of tumor Ags
• loss of MHC expression
• defect in Ag processing machinery (ie: downreg of TAP1, the transporter ass'd with Ag processing)

deletion: immune cells are deleted by apoptosis triggered by tumor

• expression of pro-apoptotic molecules by tumor cells (ie: Fas L)

anergy: immune cells undergo unresponsive status

• lack of costim molecules on tumor cells
• insufficient expression of costim molecules on APC for the priming of tumor reactive T cells (due to a lack of "danger signal" such as TLR stimulation)

suppression:immune cells are exposed to immunosuppressive mechanisms at the tumor microenvironment

• expression of inhibitory cosignals on tumor (B7-H1, B7-H4)
• presence of tumor derived immunosuppressive factors (TGF B, PGE)
• suppressive immune cells in tumor microenvironment (Tregs, myeloid suppressor cells)

what are common inhibitory cosignals expressed on tumor cell or APC?

B7 H4

B7 H1

antibody based immunotherapy

anti-EGFR mAb

approved for colorectal, head, neck cancers

antibody based immunotherapy

anti-Her2/neu receptor mAb

used for: metastatic breast cancer

antibody based immunotherapy

anti-CD20 mAb

used for: B cell lymphoma

• attenuation of receptor functions
• trigger ADCC
• tumor cell apoptosis induced C'-dept cytotoxicity (CDC)

IL 2, IFN gamma, IFN a

anti tumor efficacy is not striking (10-15% objective response)

substant side effects

more localized and concentrated production at the tumor site