Evading Immune Responses

carcinoma?

cancers of epithelial cells

ibritumomab?

CD20 Non-Hodgkin's lymphoma conjugated through the chelator tiuexetan to indium-111 for imaging and yttrium-90 for treatment

tositumomab?

CD20 non-hodgkin's lymphoma conjugated to iodine-131

gemtuzumab?

CD33 acute myelogenous leukemia conjugated to ozogamicin, a cytotoxic antibiotic derivative

alemtuzumab?

CD52 differentiation Ag CLL has an L in it... C"LL"

panitumumab?

EGFR GF receptor colorectal cancer colorectal cancer in your "pan(i)t"s

cetruximab?

EGFR GF receptor colorectal cancer, head/neck cancer colorectal cancer makes it hard to "cet"

trastuzumab?

HER2/neu protein GFR breast cancer

tumors associated with HIV-1 and HHV8?

Kaposi's sarcoma

antigens commonly mutated in cancer?

Some examples of this class of tumor Ag's are shown in this table. Identified by studying T cell responses to different types of cancers. 5 are peptide Ag with point mutation (pink). *3 are novel proteins made by fusion of 2 other proteins like BCR/ABL*. HLA molecules that present peptide Ag or restricts immune response is also shown.

process by which conjugated monoclonal Ab's detect and treat cancer?

The antiCD33 Ab coupled to inactive toxin oxogamicin. Gemtuzumab used to treat *acute myelogenous leukemia*. *Toxin activated after conjugate bound to tumor cell surface and internalized into lysosome*. Cleaved from Ab and *travels to nuc to damage DNA > adv is minimal toxicity to patient* because *toxin not active until Ab binds and is internalized in tumor cell*.

A scientist is developing a new monoclonal Ab therapy for the treatment of colorectal cancer. Which of the following molecules should the monoclonal Ab target to provide the most specific therapy for the cancer?

Tumor-specific Ag for colorectal cancer

bevacizumab?

VEGF growth factor promoting angiogenesis colorectal cancer, non-small cell lung cancer be"v"acizumab -- V VEGF

what does survival of cancer patients directly correlate with?

adaptive immune response extent within the mass!

monoclonal Ab?

antibodies produced by a single B cell clone and thus are all identical in structure and antigen specificity *monoclonal Ab's detect and treat cancer* Monoclonal Ab's specific for tumor Ag used in tumor analysis and therapy. Location of tumor cells in body revealed by *giving patients purified monoclonal Ab specific for a tumor Ag that has been covalently coupled to radioactive isotype like iodine 131*. *binding Ab to tumor cells concentrates radioactivity at sites containing tumors*. *Size/location of primary tumor can be determined as can extent of metastases*. Can help with type of therapy required to eradicate the tumor.

oncology?

branch of medicine dealing with tumors

sarcoma?

cancers of other cell types

mutagen?

chemical or physical agent that damage DNA in such as way as to cause an increased rate of mutations

BCR-ABL fusion protein as the source of peptide antigen leads to what disease?

chronic myelogenous leukemia

what are the best effector cells for killing tumor cells?

cytotoxic CD8 T cells (NK cells are good but tumor can evade response!)

tumor suppressor genes?

encode proteins that prevent the unwanted proliferation of mutant cells

proto-oncogenes?

genes that normally contribute positively to the initiation and execution of cell division

p53 as the source of peptide antigen leads to what disease?

head and neck squamous cell carcinoma

tumors associated with hepatitis B virus?

liver cancer (hepatocellular carcinoma)

how many mutations are required for cancer development?

multiple! Shows development of colorectal cancer by successive mutations in different genes.

carcinogen?

mutagens that are *known to increase the risk of cancer*

oncogenes?

mutant forms of proto-oncogenes that contribute to malignant transformation Oncogenes are the MUTANT forms of proto-oncogenes.

what are the most common reasons for malignant transformation?

mutations in tumor suppressor genes and proto-oncogenes

what are the 3 DNA viruses that can lead to cancer?

papillomavirus (many distinct strains) hepatitis B virus epstein-barr virus

how do human oncogenic viruses work?

set up chronic infections in cell that make novel virally encoded proteins that interfere/override the cell's normal mechanisms of regulating cell division. infected cells, therefore, start to proliferate encode proteins that prevent normal tumor suppressor mechanisms from acting within infected cells. other chronic infections cause cancer due to tissue damage that necessitates high rate of cell division, mutations accumulate more rapidly. (Hep B and C viral infections --> cancer might be of this type! same with stomach cancers associated with ulcers caused by infection) important: many more people become infected with these viruses than will develop cancers associated, indicating this is a MULTIPLE step process dependent on more than simple viral infection

what's an important difference of immune response to cancer compared to viruses?

tempo! *Mucosal surfaces, there is a chronic response to local microbial population* that'll readily *activate both innate/adaptive immunity when potential pathogens breach mucosal barrier*. *Other tissues: innate/adaptive immune response started by inflammation at initial site of infection*. These mechanisms make *innate immune mechanisms available within hours* after start of infection. *Adaptive fully operational within 2 weeks*. Comparison: *malignant transformation of single cell that marks the start of a cancer might go unnoticed by the body*. For *years, the growth of cancer might cause no damage that triggers inflammation*. *Growth of cancer begins to damage healthy tissues and raises alarm* for inflammation. Some cases: *immune response control/eliminate before cancer is detected*. Others: *tumor load so great immune system is overwhelmed*. As with infection, likely that *potentially cancerous cells detected by immunosurveillance and eliminated at early stage* before any perturbing effect on anatomy/function of body. *Only small minority of such cells is able to grow multiply and give rise to clinical cancer*.

how are cancers distinguished?

tissue of origin and state of differentiation

oncogenic virus?

viruses that have the potential to transform cells and promote tumor formation viruses are associated with 15% of human cancers

tumors associated with papillomavirus?

warts (benign) carcinomas of uterine cervix

malignant transformation?

when a cell has mutated such that it has become cancerous

tumor?

(swelling) = neoplasm (new growth) Tumor and neoplasm are used *synonymously to describe tissue in which cells are multiplying abnormally*. Tumors can be *benign like warts* encapsulated. Or *malignant which can continually increase size, break through basal lamina and invade adjacent tissues*.

what is the role of MHC in immune recognition of tumors?

*Tumors of lab mice will grow when transplanted into mice of identical MHC type (autologous)* but *fail to take hold in different mice of different MHC types*. In these animals, the *tumor cells are killed by alloreactive CD8 T cells*, *CD8 T cells that recognize foreign MHC*. *Human tumor cells are easily killed by alloreactive CD8 T cells* but will *also survive passage to HLA compatible person* - has occurred in some *transplant patients*. ex: 2 kidneys from deceased women given to different recipients. *Both had metastatic melanoma*. Not coincidence. 16 years before transplantation the donor had been successfully treated from primary melanoma and was considered free of tumor cells. On the contrary, she *seems to have retained some tumor cells that were controlled by her immune system*. when these *tumor cells were transferred in donated kidney to immunosuppressed transplant patients, released from immunological restraints and free to grow uncontrollably*. Confirms the point that *immune surveillance critical for controlling/limiting cancer cells*.

what are the 3 cancers of the immune system?

*leukemia* -- cancer of circulating immune cells *lymphoma* -- solid lymphoid tumors *myeloma* -- tumor of plasma cells in the bone marrow

what are the conjugated monoclonal Ab's used in the treatment of cancer?

- gemtuzumab - ibritumomab - tositumomab GIT rid of cancer A second use of monoclonal Ab *does not rely on natural effector functions of Ab*. Used to *deliver toxic agent that kills cells to which the body binds*. 3 such Ab's have been approved for clinical use

tumor-associated antigen?

antigen expressed on tumor cells but also found on normal cells, often in smaller amounts

immunosurveillence or cancer immunosurveillence?

the ability of the immune system to detect/eliminate tumors at an early stage

what are the monoclonal Ab's used in the treatment of cancer?

- rituximab - trastuzumab - alemtuzumab - cetruximab - panitumumab - bevacizumab Humanized monoclonal Ab are increased use as treatment for cancers. *5/6 Ab's shown here are specific for cell surface molecules that target tumor cells for killing by Ab dependent cell mediated cytotoxicity or opsonization and phagocytosis*. *Ab specific for VEGF has different effect*. Neutralizes this cytokine and *prevents angiogenesis* necessary for tumors to grow. Prevents tumors from generating blood supply necessary for their continued growth.

what's yet ANOTHER way that tumor cells can evade the immune response?

1. cleave MIC on surface, can't be recognized by NK cells. 2. downregulate MHC class I, less recognized by CD8. (however, they CAN be recognized by NK cells!) *3. tumor cells can evade immune response by causing anergy in tumor specific T cells through lack of costimulation*

how are novel tumor antigens generated?

Another way in which novel peptide Ags or tumor specific Ags can be produced from self proteins is by peptide splicing. In this case small fragments of peptides from a protein can be spliced out and recombine to form novel peptide fragments. Because they aren't normally produced, loaded into MHC and recognized by T cells as foreign.

tumors associated with Epstein-Barr virus?

Burkitt's lymphoma (cancer of B lymphocytes) nasopharyngeal carcinoma B-cell lymphoproliferative disease

common tissues of cancer origin in the USA?

Cancer cells can be *carried by lymph/blood to distant sites where they initiate new foci of cancer outgrowth*. Mode of spreading = *metastases*. *Site of origin primary tumor*. *Sites of spreading secondary tumors*. Cancers *most commonly in tissues actively undergoing cell division*. Most likely to accumulate mutations. Epi linings GI tract, urogenital tract, mammary glands.

Mechanisms of immune evasions by cancers?

Cleavage of Mic proteins on tumor cells and internationalization of NKG2D by NK cells and γδ T cells. Down regulation of MHC class I to evade CD8 T cells. Down regulation of tumor antigens so they are undetectable by CD8 T cells. Lack of costimulatory molecules on antigen presenting cells, resulting in anergic T cells. Recruitment of Tregs to the tumor environment, and production of cytokines (TGFβ and IL-10) to suppress antigen-specific T cells in the tumor environment.

vaccination with tumor antigens?

Knowing the *immune system has potential to make a response to kill tumor cells* but *poorly triggered for effective immune response*, tumor immunologist exploring ways to *stimulate and enhance human immune responses to cancers*. *Cancer vaccines for treatment and prophylaxis*. Trials with *malignant melanoma aggressive skin cancer with no reliable treatment*. Using *tumor specific Ag identified from melanomas, used as vaccines* to *stimulate immune response to eliminate the tumor*. Before vaccination, patient had surgery to remove cutaneous melanoma. 2 months later developed metastases that again express this tumor specific Ag. Over 2 years patient vacc 11 times, with a recombinant virus encoding epitope of tumor specific Ag. *As a result of vacc: frequency of tumor specific cytotoxic T cells increased 30 fold*. There was *steady regression of tumor to produce complete remission that lasted more than 2 years*. Reasons not understood: *tumor regression seen in only 20% patients and remission only 10%*. Several ongoing clinical trials focused on vacc with other novel tumor specific Ag in hopes you can *generate immune response to stimulate strong T cell and B cell responses that can eradicate the tumor*

An epithelial cancer cell line has been shown to have no MHC class I expression. What cell type is most likely to lyse this epithelial cancer cell line?

NK cells

another process by which conjugated monoclonal Ab's detect and treat cancer?

There are 2 humanized monoclonal Ab for CD20 - molecule on surface of B cells. Anti CD20 Ab's conjugated to radioactive isotypes used to treat nonhodgkins lymphoma can be conjugated to NDM111 or iodine 131. the adv of these radioactive Ab conjugates is their greater precision -- radiation does not have to pass through and damage other tissues to reach tumor, generated directly at surface of tumor cells, achieving high specificity and preserving normal tissue

A liver biopsy is taken from a patient, revealing a small tumor. The cancer tissue has high expression of MHC class I molecules, no evidence of inflammation, and no tumor-specific effector T cells were found in the tissue or in the blood of this patient. What is the most likely conclusion?

Tumor-specific CD8 T cells failed to develop due to lack of costimulatory molecules

even MORE ways by which tumors can evade the immune response?

Tumors can manipulate immune response to favor their survival. Often *make antiinflammatory cytokines like TGF-beta*. *Inhibits proliferation and cytokine production in Th1 cells*. *Inhibit lytic granules from CD8* and their proliferation too. *Neutralizes function of both CD4 and CD8 T cells in the tumor environment*. Another T cell not spoken of and they are *Tregs --regulatory T cells*. Another population of T cell that plays role in *limiting function of effector T cell populations*. Tregs *downregulate CD4 effector and cytotoxic CD8 T cells*. Do in couple of manners. One is to *produce antiinf cytokines like TGF-beta, IL10* that *prevent T cell proliferation and minimize cytokine production and production of lytic granules by CTLs*. This *favors env in tumor that favors its survival* by limiting effector T cell functions.

explain the evasion of the immune response by tumors?

When an *immune response is made against tumor, it imposes selection on the population of tumor cells*. *Variant cells that have low expression of tumor specific antigens or mutant epitopes that are no longer recognized by effector T cells/Ab may be able to evade immune response*. The *longer a cancer grows*, expands population, and colonizes different sites/env in human body, the *more genetic variation it acquires*, and the *less likely it becomes that the immune response can delay/terminate the disease*. *Thus the immune system has its best chance of eliminating a cancer in its early stages*. Population of *cancer cells is small and has yet to adapt to immune response*. *NK cells recognize STRESSED cells*. Many *cancer cells have stress responses and upregulate the MIC proteins*. MIC proteins are *ligands for NKG2D receptor* on NK cells, as well as *gamma-delta T cells*. Expression of MIC *enable NK cells to attack/kill tumor cells*. If done efficiently, *tumor is driven to extinction*. If *only a fraction of the tumor cells are killed, the remainder has ability to proliferate and acquire changes/mutations in gene expression that allow them to evade immune response*. *Some successful epithelial tumors make proteases that cleave MIC proteins* (3) from surfaces *producing soluble form that binds NKg2D receptor on NK cells on gamma delta T cells* and *NK induces rec mediated endocytosis, removing NKg2D from surface and speeds its degradation*. By *removing MIC from own surfaces and NKg2D from lymphocyte surfaces, tumor cells evade attack from NK cells and gamma-delta T cells and thus survive*.

tumors associated with HTLV-1?

adult T-cell leukemia/lymphoma

mutations?

alterations in DNA Maintaining the human body involves continuing cell dividing to *replace worn out cells, repair damaged tissues, mount immune responses* against invading pathogens. 10^16 cell div occur in body in lifetime. Essential *prep for division is DNA replication* making 2 identical copies of diploid genome. *Proofreading mechanisms. Rare errors still made*. Additional *change arise from chemical damage that escape repair machinery*. *Changes in DNA are called mutations*. They include *substitution, insertion, deletion nucleotides, recombination between different members of gene families and chromosomal rearrangements*. *Mutations in germline (egg and sperm) provide variation that allow human species to diversify*/evolve. *Somatic mutations are mostly never noticed* since effects manifested in single cell. Only in 1 individual. *Certain mutations abolish normal control of cell division/survival*. Mutant cell proliferates to form expanding population of mutant cells that *disrupt body normal function causing disease collectively called cancer*.

tumor-specific antigen?

antigen expressed on tumor cells but not on normal cells *Almost all cancer patients make adaptive immune response against their tumor*. The *antigens to which they respond = tumor antigen*. Study tumor reactive Ab and CD8 T cells made by patients with different types of cancers, more than 1000 different Ags found. Antigens on tumor cells but not normal = tumor specific. *Tumor specific Ag have structures not present in normal cells*. Can be *derived from viral proteins, from mutated parts of mutant cellular proteins, or from aa sequences spanning tumor specific recombination sites between genes*. *Tumor specific Ag are the primary targets of CD8 T cells and Ab* in controlling tumor burden.

alloantigens?

antigen that differs between members of the same species, such as *HLA molecules*. alloantigens are recognized *as foreign* and elicit adaptive immune responses to eradicate the antigen.

rituximab?

antigen: CD20 function of Ag: B-cell signaling receptor treats Non-Hodgkin's lymphoma

3 ways in which tumors can evade immune response?

cleave MIC decrease MHC class I no costimulation by APCs

what are RNA viruses that can lead to cancer?

human T-cell leukemia virus type 1 (HTLV-1) human immunodeficiency virus (HIV-1) and human herpes virus 8 (HHV8)

name the common characteristics of cancer cells?

increased incidence of cancer among transplant patients maintained on *immunosuppressant* drugs, showing that the immune system can control/eliminate cancer cells

how does #3 (above) occur?

left: if a tumor Ag is presented by an activated macrophage or mature DC, *B7 (CD80/86) will be present on the APCs* and the tumor-specific CD8 T cell will be able to become activated and kill tumor cells! NEED the costimulator though. Right: however, the APCs are often *not activated by tumors* and therefore, the APCs remain in an immature or inactivated state. these APCs *will not express the costimulator molecule B7 (CD80/86)* and therefore, T cells specific for the tumor antigens will not become activated. they will *become anergic or unresponsive*, allowing the tumor to go undetected by CD8 T cells! Tumors can evade immune response by *causing anergy in tumor specific T cells through lack of costimulation*. Left is ideal stimulation of Ag presentation of tumor Ag to T cell. Ag presenting cell should be activated mac/DC that expresses B7 costim molecules so tumor specific T cell gets *signal 1: tumor Ag presented by MHC to TCR* and *B7 by CD 28*. act T cell, CD8+ T cell *can then lyse tumor cells that are expressing tumor spec antigens*. Many cases there is *not significant inflammation at tumor site and Ag presenting cells like macs/DCs do not get activated/mature and don't express costim molecule B7*. in this case there's *no second signal/costimulation* so even though tumor Ag can be presented by MHC to tumor specific T cell there's *no act of T cells* and the *T cell becomes adrenergic* -- unresponsive and fails to become activated. Mechanism by which tumors can evade development of tumor specific T cells.

what does malignant transformation do to cancer cells that enables them to be recognized by the immune system?

like viral infections, malignant transformation *alters protein expression in cancer cells and makes them appear foreign to immune system* *changes in expression of MHC class I molecules* that can be detected by *NK cells of innate immunity and CD8 T cells in adaptive immunity*. so, the mechanism for cancer immunosurveillance is the SAME for those used for detecting/responding to viral infections.

what's another way that tumor cells escape immune response?

we already learned that one way they do so is cleaving MIC on their surfaces so they cannot be recognized and NK cells endocytose their NKG2D receptors. another way tumor cells escape the response is *diminish expression of Class I molecules that present tumor specific Ag to CD8 T cells*. Between *1/3 and ½ all human tumors have defective expression in 1+ of HLA class I molecules*. Figure bottom left: cancer, MHC stained with brown. Brown coloring quite sparse, yet *normally all cells in tissue should be class I positive*. This tells us that *many patients have successfully made CD8+ T cell responses against their cancer but variant cells have downregulated class I expression and allowed them to escape immune surveillance by CD8 T cells allowing cancer to continue to grow*.

what else can the loss of HLA class I do?

we learned that (1) it can lead it to not be able to be recognized by CD8 cytotoxic T cells, but also (good thing)... The *loss of HLA class I expression can make a tumor susceptible to attack by NK cells*. remember this mechanism... we learned it before!!! *Killing of acute myelogenous leukemia cells by alloreactive NK cells in HLA haploidentical bone marrow transplant* occurs because *recipient tumor cells lack HLA class I allotype that the donor derived NK cells can see as self*. Example of NK cells attacking cell that is missing self.