BL.2.13: Tumor Immunology, Neoplasms Mature Lymphoid Flashcards
State the concept of the Immune Surveillance theory. Discuss whether data from immunosuppressed and immunodeficient patients support the theory.
The true role of the immune system, especially of T cells, would be to constantly monitor the surfaces of cells in the body; if one was detected as abnormal, that cell would be destroyed before a mutant, possibly malignant, clone developed.â–ºPeople with immunodeficiencies, particularly of T cells, have a higher incidence of tumors, e.g. AIDS patients have a higher rate of Kaposi’s sarcoma.Activated T cells that recognize tumor-associated antigens can be identified. The presence of lymphocytes in a tumor (tumor-infiltrating lymphocytes or TIL) is a good prognostic sign.A small percentage of tumors, mainly melanomas, spontaneously regress, presumably due to an immunologic response.
Describe the concept of immunoediting.
Elimination: â–ºSomething must be eliminating most cells that get initiated by a mutagenic event. For an immunologist, that thing would be immune surveillance. The idea is that when a clone becomes malignant its most likely fate is to be recognized as abnormal by both the innate and adaptive immune systems, and thus eliminated.Equilibrium: In most clinically relevant tumors, T cells infiltrate the tumor, but do not fully destroy it. Instead the tumor and T cells exist in an equilibrium. â–ºBut equilibria are often dynamic, and changing conditions—the host’s immunity drops for some reason, or further mutations accumulate in residual tumor cells—can eventually lead to reactivationEscape: Tumor cells can fight back! Blocking factor in serum can prevent T cells from killing tumors. â–ºTumors evolve many escape mechanisms. Some modify their tumor-associated antigens until the host does not have T cells against them with highly avid receptors. Others make immunosuppressive factors like TGFβ. And almost all, as they progress, reduce the expression of MHC Class I so there is less and less for CTL to recognize.
Describe tumor-associated antigens (TAA), and compare and contrast TAA from viral, mutant, and normal gene products.
All tumor cells can be shown to have antigens that are not readily found on the corresponding normal cell. Often they are found on normal cells, but in much lower quantities; they are overexpressed or abnormally expressed by the tumor. â–ºSuch antigens are called tumor-associated antigens (TAA). A subclass of TAA are those that can be recognized by the immune system, in a way that leads to the destruction of the tumor. Such antigens are called tumor rejection antigens.Lots of tumors are caused by viruses, like HPV causing cervical cancer.Mutant gene products: abnormal proteins are created by carcinogens, these get presented on cells, and create tumor specific antigens. Unfortunately, these can vary from person to person so not easy to treat.Normal gene products: A good example is oncofetal antigens which are made normally in fetuses and not in adults. Often, they are expresed in tumors. Other examples are differentiation antigens (EGFR, HER2) and clonal antigens (TCR).
Define carcinoembryonic antigen (CEA) and discuss its usefulness in screening for, diagnosis, and follow-up of colon cancer.
Carcinoembryonic antigen (CEA), a common oncofetal antigen, is found in the blood of patients with colon carcinoma and other cancers.There are commercially available kits to detect CEA in blood. They should not be used as a routine screening test. Why not? Too many false positives.The proper use of CEA measurement comes when you have a high index of suspicion of colon cancer; or, when such a cancer has been removed, to confirm complete excision (levels fall to 0 and remain there) or to warn of recurrence.
Compare and contrast the roles of CTL and NK cells in killing tumors cells, with special reference to the amount of MHC Class I expressed by the tumor.
CTL (CD8+): Hangs out in lymph nodes (naive), gets presented to, goes to the tumor, kills it (ideally) and secretes INFgamma. They bind cells with lots of MHC1, presenting TAAs, and kill them.NK cells: see stress” signals on cells like rapid division. It wanders over
Describe the nature and therapeutic use of tumor-infiltrating lymphocytes, TIL, in adoptive cellular transfer therapy.
This technology utilizes cells from the patient’s immune system to destroy cancerous cells that cannot be surgically removed. Cells from the immune system that have potential to fight the tumor are isolated from the patient’s blood, tumor, or lymph nodes. â–ºCells directly from the tumor are called tumor-infiltrating lymphocytes (TIL). The T cells are expanded greatly in culture using cytokines such as IL-2. The patient’s immune system may then be partially destroyed by irradiation to make “room” for the expanded anti- tumor clones. They are reintroduced into the immune-depleted patient to kill remaining tumor cells.
Summarize the Hellstrom experiments using cells from tumor- bearing and cured patients to kill tumor target cells. Indicate which patients had blocking factors. Discuss the possible nature of blocking factors.
Melanoma + regressive person’s T cells = tumor deathMelanoma + progressive person’s T cells= tumor deathMelanoma + anyone’s T cells + progressive serum = tumor survival due to blocking factorsBlocking factors prevent T cells from killing cancer cells. Perhaps they create an immunosuppresive environment.
Discuss the principles underlying antibody or T cell methods that might be used as treatments of tumors.
Antibody to TAAs should be useful, and quite a few monoclonal antibodies (mAb) are already available. They can be used as-is (possibly they activate complement, and the tumor is lysed or phagocytosed; more likely they invoke ADCC), or they can be tagged with a poison such as ricin, or diphtheria toxin, or a radioisotope (such modified antibodies are called immunotoxins).T-cells can bind bad things and kill them, so if they could bind a tumor, they could call macrophages, and induce apoptosis.
Describe a mechanism by which BCG treatment causes tumor regression.
Innocent bystander killing. BCG is injected directly into the tumor. A ferocious delayed-type hypersensitivity reaction to BCG ensues, and the tumor cells are killed the way lung is killed in TB. This is used to some degree in cutaneous tumors like melanoma, and â–ºBCG instilled directly into the bladder is the treatment of choice for superficial bladder carcinoma.
Discuss the three most common B-cell neoplasms.DLBCL:size(s) of the cell,the patterns of this neoplasm,how prognosis is determined.
Diffuse large B-cell lymphoma (DLBCL):The lymphoid cells of DLBCL, NOS are large; >= macrophage nucleus, or about the size of two small mature lymphocytes.Typically patients present with a rapidly enlarging mass that can be at one of multiple sites, including extranodal sites. The GI tract is the most common extranodal site involved but no site is immune. Also possible bone marrow involvement.DLBCL, NOS is an aggressive lymphoid neoplasm. The International Prognostic Index has proven to be successful in predicting prognosis.
Discuss the three most common B-cell neoplasms.Follicular lymphoma:size(s) of the cell,the patterns of this neoplasm,how prognosis is determined.
The neoplastic germinal centers in FL contain a more monotonous population of cells – centrocytes or centroblasts, or a mixture of the two with one, usually centrocytes, predominating. (size not mentioned)The neoplastic follicles are packed closely together and lack the cuff of small mature lymphocytes that surround normal germinal centers (the mantle zone). Thus when lymph node architecture is effaced by neoplastic germinal centers the pattern is called follicular.The International Prognostic Index (IPI) (or a version of the IPI modified for FL) is very good at predicting how a patient with FL will fare. Grade 3 FL is significantly more aggressive than Grades 1 and 2 FL. Grades 1 and 2 FL are relatively indolent diseases.
Discuss the three most common B-cell neoplasms.Chronic lymphocytic leukemia/small lymphocytic leukemia:size(s) of the cell,the patterns of this neoplasm,how prognosis is determined.
The predominant cell in CLL/SLL is a small (a small lymphocyte has a nucleus smaller than a macrophage nucleus), round to slightly irregular mature B-cell. There are lesser number of larger B-cells with nucleoli called prolymphocytes and paraimmunoblasts.;the leukemic cells may form nodules in the bone marrow, or there may be a diffuse infiltrate of leukemic cells in the bone marrow.In the lymph node there is a diffuse infiltrate of the small cells. Interspersed in this diffuse infiltrate are nodule like aggregates of prolymphocytes and paraimmunoblasts called pseudofollicular proliferation centers.The International Index is a prognostic factor model that associates several well- defined risk factors with prognosis.
Of the 3 most common mature lymphoid neoplasms, which has a fairly distinctive cytogenetic finding?Discuss this cytogenetic abnormality in terms or the genes involved, its role in the pathogenesis of the neoplasm, and how it affects the immunophenotype of this neoplasm.
In Follicular Lymphoma t(14;18)(q32;q21) involves a reciprocal translocation of the BCL2 gene to the immunoglobulin heavy chain gene transcriptional enhancer.The product of the BCL2 gene is the anti-apoptotic protein BCL2. The BCL2 gene is “switched off” in normal germinal center cells. The translocation causes the BCL2 gene to be abnormally “switched on” conferring extended survival to germinal center cells.Over-expression of the BCL2 anti-apoptotic protein is the primary oncogenic event in FL.Immunophenotypic Result: As a result of t(14;18)(q32;q21) the BCL2 protein will be expressed by FL.
Describe what is meant by stage 1, stage 2, stage 3, and stage 4 in the Cotswald modification of the Ann Arbor staging system. What are B symptoms”?”
B symptoms refers to 3 signs and symptoms (fever, drenching sweats, and weight loss).
Describe how and when the International Prognostic Index is used.
Assign points based on risk factors then look up in table below. Used for FL, CLL/SLL, and DLBCL, NOS.
