Flashcards in BL Tumor Immunology last one!!! Deck (19):
concept of the Immune Surveillance theory
○ Adaptive immune response is NOT for for dealing with foreign substances
○ Instead it is a way to detect changes to self due to damage or mutation
○ T-cells are supposed to monitor the surfaces for anyone who is abnormal. Kill them before they can make a mutant malignant clone
- close but no dice: it does however tell us our immune system plays an important role in inhibiting tumors
is a series of stages in a process
The three "Es" of immunoediting
Elimination mechanism in immunoediting
If a clone becomes malignant (transformed), then it is abnormal and becomes recognized and eliminated
i. Recognized because it has abnormal metabolic activity → DAMPs activate innate immunity
ii. Activate T cells, macrophages and CTLs infiltrate the tumor
iii. If the clone is killed, the process ends. Otherwise… proceed to step 2 (equilibrium)
Equilibrium mechanism in immunoediting
Because most tumors aren't killed by lymphocytes, they are thought to exist in equilibrium.
i. As long as the immune response is strong, the virus is kept at bay
ii. If the immune response is strong, tumor doesn't develop further
As soon as the host's immunity falls, mutations can accumulate and lead to reactivation
CTLs 2 "checkpoint inhibitor"
CTLA-4 and PD-1
-Initially the CTLs can kill most of the tumor cells, but a few will survive and proliferate.
-Eventually the entire tumor will become CTL resistant!
• These are checkpoint inhibitors - Tumors can take advantage of them and upregulate these checkpoint inhibitors
TSA (Tumor-specific antigen):
tumor cell antigens not found on normal cells. Easy to target
TAA (Tumor-associated antigens)
tumor cell antigens found on normal cells but more common or weird looking on tumor cells. Harder for the immune system to target
TRA (Tumor-rejection antigen)
a sub-type of TAA that can be recognized by immune system and lead to destruction of the tumor
carcinoembryonic antigen (CEA)
an oncofetal antigen found in the blood of patients with colon carcinoma
Most important cell in tumor resistance
CTL killing tumor cells: ( It makes IFNγ and can bring in macrophages…)
CTL mechanism in killing tumor cells
1. Recognize TAA that is presented by MHC class I → activates T cells in lymph nodes via DCs.
2. The CD8+ T cells proliferate (clonal expansion) and then activate
3. The TAA-specific cells migrate to the tumor and induce apoptosis
a. Either by Fas-mediated pathways
b. Or by perforin
c. Also stimulates macrophages by secreting IFNγ
Th1 cells mechanism in killing tumor cells
1. CD4+ T cells recognize tumor antigens
2. Make lymphokines → attract angry M magrophages
3. Recall that Th1 can also help activate CTLs
• Tumors try to avoid the M1 environment. They prefer a protective M2 environment instead.
NK cells mechanism in killing tumor cells
• Called large granular lymphocytes LGLs
• Do not need to come from an immunized host
• Part of innate immunity
1. Recognize "stress-related" markers on tumor cells
2. Down-regulated if there is MHC Class I
(If a lot of Class I, then make CTLs so you don't need NK)
• Tumor makes lots of Class I? use _____ cells
• Tumor stops making Class I? use ____ cells
Tumor makes lots of Class I?
Tumor stops making Class I?
therapeutic use of tumor-infiltrating lymphocytes, TIL
Adoptive cellular transfer therapy.
• TILs are cells directly from the tumor
• They are expanded in culture using IL-2 while the patient's immune system is being irradiated
• You can now insert the anti-tumor clones and let them run around to kill the tumor
Use of mAb against PD-1 and CTLA-4
• Can make a monoclonal Ab against PD-1 which binds and blocks CTL inactivation
○ Recall that PD-1 reduces cytotoxic activity
• Can also make ipilimumab to block CTLA-4
○ Recall CTLA-4 is a downregulator of CTL activity
the mAb then is able to upregulate T cell activity to kill the tumors!
T cell methods that might be used as treatments of tumors
• A vaccine that uses the patient's own DCs with a fusion protein containing the cancer TAA
• New ones also include epitopes with a higher affinity to the MHC or TCR
• Mostly associated to cytokine TNF, where macrophages and neutrophils can come in and eat away.
Antibody methods that might be used as treatments of tumors.
• Can possibly:
○ Activate complement
○ Invoke ADCC
○ Or tagged with a poison (immunotoxins)
• Also can use antibodies to growth factors to stop self-stimulating (autocrine signaling)
○ Example is anti-IL-2 receptor in T lymphomas
○ Herceptin is another, a mAb to HER2 on breast cancer