BL 03-06-14 11am-Noon Tumor Immunology - Cohen Flashcards
Cancer - epidemiology
- 2nd leading cause of death in US (after heart disease)
- 2nd leading cause of years of life lost (after accidents)
- BUT, US cancer death rates decreased between 2002 & 2008 (in the rest of the world, rising)
Mutations in humans
- human will undergo up to 10^16 mitoses in a lifetime
- mutations happen at a rate of 10^-8 / bp / mitosis
- –> 3000 mutations/hr
- about 1 per hour is potentially oncogeneic
Immune Surveillance
The view of Lewis Thomas in 1959, that the adaptive immune response evolved not so much for dealing with foreign substances, but as a way of detecting changes in the body’s own cell surfaces.
- These changes would probably be due to damage or mutation.
- The true role of the immune system, esp. of T cells, would be to constantly monitor cell surfaces in the body
—> if one was detected as abnormal, that cell would be destroyed before a mutant (possibly malignant) clone developed.
= incredibly ahead of its time, since T cell’s preoccupation with “self” was not discovered for ~20 yrs
- Looked at in this light, the development of cancer could be seen as a failure of immunity.
Evidence for cancer immune surveillance
- Ppl w/ immunodeficiencies, esp. of T cells, have a higher incidence of tumors
- AIDS patients
- Organ transplant recipients
- People treated w/ chemotherapy - Activated T cells that recognize tumor-associated antigens can easily be IDed
- Small % of tumors (mainly melanomas & some lymphomas) spontaneously regress, presumably due to an immunologic response.
Tumor-infiltrating lymphocytes (TIL)
= activated T cells that recognize tumor-associated antigens
- presence of lymphocytes in a tumor (TIL), many of which are tumor-specific, is a good prognostic sign.
Limitations to immune surveillance hypothesis
- Tumors that immunodeficient/suppressed ppl get:
- NOT a random sample of all tumors that can occur
- rather, tend to be tumors of lymphoid system & of the skin, but rarely lung or breast - Nude mice (mice w/ no thymus)
- should get tumors very readily
- BUT in fact spontaneous tumors are rare
- Why? Probably b/c these mice have very high levels of NK cells, which are not part of traditional (T & B cell) immune system but can be quite tumoricidal (directly or via ADCC)
Immunotherapy in Cancer
- B/c of shortcomings, immune surveillance hypothesis fell somewhat into disrepute.
- But newer ideas have revived the study & application of immunological principles to cancer
- Compared to traditional cancer treatment modalities (radiation, chemo, surgery) immunotherapy promises the new concept of specificity.
Immunoediting
One can think about the role of the immune system in neoplastic development as a series of stages in a process that has been called “immunoediting.”
Stages:
- Elimination
- Equilibrium
- Escape: the tumor cells fight back
Why Immun Surveillence must be involved in the Elimination step of Immunoediting
Going from 1 cell to 1 gram of tumor (109 cells) is 31 generations.
- would take 30 days if tumor cell cycle were 24 hrs
- BUT epidemiology suggests it takes ~20 years!
- –> implies cycle time of 240 days = unreasonable
Something must be eliminating most cells that get initiated by a mutagenic event.
= immune surveillance?
Immunoediting - Step 1 - Elimination
When clone becomes malignant, most likely will be recognized as abnormal by both innate & adaptive immune systems
—> eliminated
Tumor cells exhibit a variety of metabolic abnormalities compared to normal cells
- –> expression of DAMPs
- –> activate innate immunity
Cytokine secretion & Ag presentation on DCs activate T cells
—> macrophages & CTLs infiltrate tumor
If the abnormal clone is successfully eradicated, process ends.
Immunoediting - Step 2 - Equilibrium
In most clinically relevant tumors, lymphocytes infiltrate tumor, but do not fully destroy it.
- Instead tumor & lymphocytes exist in equilibrium.
May be analogous to situation w/ Epstein-Barr virus in bone marrow, or Varicella in dorsal root ganglia:
- As long as immune response is strong, latent
But biologic equilibria are dynamic
- Changing conditions (drop in host immunity or further mutations accumulate in residual tumor cells)
- –> reactivation
Immunoediting - Step 3 - Escape
= the tumor cells fight back via mutations and immunosupressive mechanisms
3 Experiments to answer the question of whether the immune system has something to do with tumor regression:
Traditional cancer treatments can’t remove every last cell– so is immune system involved ?
Experiments studied pts w/ malignant melanoma:
- Some had been cured by therapy = regressors
- Most had growing tumors = progressors
EXPERIMENT 1:
- T cells from regressors added to melanoma cells
- Result: T cells killed tumor cells.
- Conclusion: As expected, if immune system really helped these people get rid of their tumors.
EXPERIMENT 2:
- T cells from pts w/ progressively growing tumors added to melanoma cells, as a CONTROL
- Result: T cells killed tumor cells.
- Conclusion: Unexpected in light of Experiment 1!
Other controls quickly showed this killing was tumor-specific in both experiments…
*Both groups really had killer T cells against melanoma; normals don’t.
So why did tumors keep on growing in progressor pts who had developed CTL against them?
- Tumor cells found means to escape surveillance.
EXPERIMENT 3:
- T cells from either group added to melanoma cells, now in presence of serum from progressor pts
- Result: NO killing.
- Conclusion: Serum contains blocking factors, which specifically block the killing of melanoma cells by melanoma-specific killer T cells
Blocking factors - types
Blocking factors include:
- shed tumor antigen (or antigen-MHC complexes)
- sometimes antibody against tumor antigens (don’t harm the tumor while shielding it from T cells)
Blocking factors - what they remind us
Existence of blocking factors (though not seen in every tumor type) is instructive:
- Reminds us that tumor & host are co-evolving systems
- –> When we see clinically-relevant tumor in pt, we know it has already come up w/variety of tricks to avoid immunity.
Escape Mechanism of Tumor cells
►Tumors evolve many escape mechanisms.
- Some modify their tumor-associated antigens (see
below) until the host does not have T cells against them with highly avid receptors. - Others make immunosuppressive factors like TGFbeta
- Almost all, as they progress, reduce the expression of MHC Class I so there is less and less for CTL to recognize.
Tumor antigens
All tumor cells can be shown to have antigens not readily found on the corresponding normal cell.
Often the tumor Ags are found on normal cells, but in much lower quantities
—> over- or abnormally expressed by tumor
►Such antigens are called tumor-associated antigens (TAA)
Subclass of TAA are those that can be recognized by immune system, in a way that could lead to the destruction of the tumor. = called tumor rejection antigens
Tumor-associated antigens (TAA)
- antigens on tumor cells that are not readily found on corresponding normal cells
- often these Ags ARE found on normal cells, but in much lower quantities
- –> over- or abnormally expressed by tumor
Tumor rejection antigens
= subclass of TAA = those TAA that can be recognized by immune system, in a way that could lead to tumor destruction
Viral gene products
Many tumors are known to be caused by tumor viruses
= ~20% of tumors in humans (directly or indirectly caused by viruses)
Tumor viruses - HTLV-1 & -2
Esp. noteworthy tumor viruses
Strongly implicated in:
- Sézary syndrome/ mycosis fungoides
- Similar epidemic lymphoma in Japan & the Caribbean
Tumor viruses - HPV
Cervical cancer (human papilloma virus) = currently best-known virally-induced human tumor
